WO2007132846A1 - Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé - Google Patents

Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé Download PDF

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Publication number
WO2007132846A1
WO2007132846A1 PCT/JP2007/059960 JP2007059960W WO2007132846A1 WO 2007132846 A1 WO2007132846 A1 WO 2007132846A1 JP 2007059960 W JP2007059960 W JP 2007059960W WO 2007132846 A1 WO2007132846 A1 WO 2007132846A1
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Prior art keywords
group
substituent
substituted
salt
solvate
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PCT/JP2007/059960
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English (en)
Japanese (ja)
Inventor
Kensuke Kusumi
Masaya Kokubo
Hiroshi Ochiai
Shiro Shibayama
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Ono Pharmaceutical Co., Ltd.
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Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to US12/301,194 priority Critical patent/US8618122B2/en
Priority to JP2008515563A priority patent/JP5257068B2/ja
Priority to EP07743395A priority patent/EP2042503B1/fr
Publication of WO2007132846A1 publication Critical patent/WO2007132846A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a compound containing a basic group which is protected by a protecting group useful as a pharmaceutical, but is substituted with an acidic group, and use thereof.
  • Chemokines are known as basic proteins that have chemotaxis and activity on endogenous leukocytes and have strong heparin-binding properties. At present, chemokines not only control specific leukocyte infiltration during inflammation and immune responses, but are also thought to be involved in development, lymphocyte homing under physiological conditions, and migration of blood cell progenitors and somatic cells. ing.
  • Activated and dissociated cutaneous Langernon cells migrate to the ⁇ -cell region of the local lymph node and activate naive T cells as dendritic cells.
  • Memory T cells home to lymph nodes and blood vessels, and then home to the lymph nodes.
  • B cells, intestinal intraepithelial T cells, ⁇ ⁇ ⁇ cells, sputum cells, and rod cells migrate and differentiate from the bone marrow without passing through the thymus and participate in immune responses.
  • Chemokines are deeply involved in the migration of such various cells.
  • SDF-1 SDF-1
  • CXCR4 (Stromal cell derived factor-1) and its receptor, CXCR4, also act on various immune and inflammatory reactions. For example, it has been reported to be involved in the accumulation and activity of CD4 + T cells in synovium from human patients with rheumatoid arthritis (J. Immunol., 165, 6590-6598 (2000)). Furthermore, CXCR4 inhibitors also suppressed the accumulation of leukocytes in the joints and dramatically reduced the arthritis score in CIA model mice (J. Immunol, 167, 4648-4692 (2001)). In a mouse OVA-induced airway hypersensitivity model, anti-CXCR4 antibody reduced the number of eosinophils accumulated in the lung stroma and suppressed airway hypersensitivity (J.
  • SDF-1 and its receptor, CXCR4 have also been reported to play an important role in the maintenance of hematopoietic stem cells in the bone marrow (J. Exp. Med., 185, 111-120 (1997). ), Blood, 97, 335 4-3360 (2001)) o Therefore, control of SDF-1 and CXCR4 is expected to regulate hematopoietic stem cell mobilization into peripheral blood, peripheral blood stem cell transplantation, and even regenerative transplantation Useful for treatment.
  • SDF-1 and CXCR4 are involved in the proliferation and invasion of various cancer cells such as breast cancer, prostate cancer, ovarian cancer, and medulloblastoma (Nature, 410, 50-56 (2001)) Res., 62, 1832-1837 (2002), Cancer Res., 62, 5930-5938 (2002), Proc. Nat. Acad. Sci.
  • anti-CXCR4 antibody suppressed tumor cell growth and improved mouse mortality (Cancer Res. ., 62, 3106-3112 (2002)) 0
  • a small molecule CXCR4 antagonist potentiated apoptosis of medulloblastoma transplanted into the mouse skull and suppressed tumor growth (Proc. Nat. Acad. Sci. USA, 100, 13513-13518 (2003)).
  • the small molecule CXCR4 antagonist has enhanced the antitumor effects of immunostimulators and anticancer agents in a lung metastasis model using malignant melanoma (Mol Cancer Ther., 5, 2592-9 (2006)).
  • SDF-1 and CXCR4 play an important role in the formation of hippocampal dentate granule cells essential for memory and learning, and diseases related to adult plasticity and hippocampal pathology, such as Alheimer's disease and stroke (Development, 129, 4249-42 60 (2002), Trends in Neuroscience, 25, 548-549 (2002)) 0
  • SDF-1 and CXCR4 are essential for the function of autoreactive B cells involved in the development of diabetes, and anti-SDF-1 antibody reduces blood glucose levels in maturation of peripheral tissues in NOD mice The number of IgM + B cells was decreased (Immunology, 107, 222-232 (2002)). In addition, SDF-1 was highly expressed in human atherosclerotic plaques and activated platelets (Circ. Res., 86, 1 31-138 (2000)).
  • SDF-1 and CXCR4 are involved in the retention of hematopoietic stem cells and hematopoietic progenitor cells in the bone marrow, and the CXCR4 antagonist AMD3100 is combined with G-CSF in the peripheral blood.
  • the number of hematopoietic stem cells and hematopoietic progenitor cells was increased (Journal Experimental Medicine, 2001, 1307-1318 (2005).
  • administration of low molecular weight CXCR4 antagonists to humans caused neutrophils, lymphocytes, monocytes, etc.
  • SDF-1ZCXCR4 knockout mice indicate that SDF-1 is essential for the functions of the central nervous tissue, heart, and gastrointestinal tract in addition to lymphocytes (Nature, 382, 635-). 639 (1996), Nature, 393, 591-594 (1998), Nature, 393, 595-599 (1998)). From this, it is considered that they are involved in diseases of these tissues.
  • chemokine receptors are expressed in various specific cells at a specific time, and when the effector cells accumulate at the place where chemokines are produced, inflammation and immunity are caused through the mechanism. It is greatly involved in the control of the reaction.
  • AIDS Acquired immune deficiency syndrome
  • human immunodeficiency virus hereinafter abbreviated as HIV
  • HIV human immunodeficiency virus
  • CD4-positive cells which are the main target cells
  • HIV repeats proliferation in the patient's body, eventually destroying T cells that control immune functions.
  • immune function gradually decreases, and various immunodeficiency states such as fever, diarrhea, and lymph node swelling are exhibited, and various opportunistic infections such as potash-pneumonia are likely to occur.
  • Such a condition is the onset of AIDS, and it is well known that it induces and makes malignant tumors such as force-positive sarcoma.
  • various prevention and Z or treatment methods for AIDS include, for example, (1) suppression of HIV growth by administration of reverse transcriptase inhibitors and protease inhibitors, and (2) use of drugs with immunostimulatory effects. Attempts have been made to prevent or alleviate opportunistic infections by administration.
  • HIV mainly infects helper T cells that are central to the immune system.
  • helper T cells that are central to the immune system.
  • the CD4 molecule has a force of 433 amino acid residues, and in addition to mature helper T cells, macrophages, some B cells, vascular endothelial cells, skin tissue Langerhans cells, lymphoid cells, central nervous system glia Expression is seen in cells and the like.
  • CD4 molecules alone did not establish HIV infection, it was suggested that there might be factors other than CD4 molecules involved in HIV infection in cells.
  • Fusin a cell membrane protein called Fusin was identified as a factor related to HIV infection other than the CD4 molecule (Science, 272, 872 (1996)).
  • This hoodin molecule is SDF— Proven to be one receptor, CXCR4.
  • SDF-1 has also been shown to specifically inhibit T cell-directed (X4) HIV infection (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). That is, SDF-1 binds to CXCR4 prior to HIV, thereby depriving HIV of a foothold for infecting cells and inhibiting HIV infection.
  • CCR5 another chemokine receptor, RANTES, MIP-1a, and MIP-1 ⁇ receptor, is also used for macrophage-directed (R5) HIV infection.
  • R5 macrophage-directed
  • a substance that can deprive HIV and CXCR4 or CCR5, or that binds to HIV virus and makes the virus unable to bind to CXCR4 or CCR5, may be an HIV infection inhibitor. is there.
  • low molecular weight compounds initially discovered as HIV infection inhibitors were actually shown to be antagonists of CXCR4 (Nature Medicine, 4, 72 (1998)).
  • compounds having a CXCR4 antagonistic action include, for example, inflammation'immune diseases, allergic diseases, infections, particularly HIV infections and associated diseases, mental'neurological diseases, brain diseases, Effective for prevention and Z or treatment of cardiovascular disease, metabolic disease, cancer disease. It is also useful for cell medicine and regenerative medicine.
  • a 1X and A 2X each independently represent a hydrogen atom, an optionally substituted monocyclic or polycyclic heteroaromatic ring, or a substituted, monocyclic or polycyclic ring
  • G 1X represents a single bond or CR 2X R 3X
  • R 1X , R 2X , R 3X may be substituted, but may represent an alkyl group having 1 to 6 carbon atoms, etc.
  • W x is replaced, by even a few 1-7 alkylene group having a carbon substituted single may or polycyclic heterocyclic aromatic ring or substituted may be monocyclic or polycyclic X x represents z lx — CO— Z 2X — etc., Z 1X and Z 2X each independently represent a single bond, NR 13X, etc., y X represents — CO etc. the expressed, each independently D 1X and D 2X, represent a hydrogen atom or a G 2X -R 4X, display the G 2X is substitutable C15 alkylene group carbon atoms which may have such And, R 4X water atom, substituted to!
  • N2X represents 0 to 4
  • NLX represents 0 to 3
  • B x represents an -NR 6X R 7X and the like. In addition, only the necessary parts were extracted from the definition of each group.
  • R 1YY , R 2YY , R 3YY , R 4YY , R 5YY , R 6YY are each independently a hydrogen atom or an optionally substituted carbon number. 1 to 15 alkyl group, etc., A 1Y and A 2Y each independently represent a monocyclic or polycyclic heteroaromatic ring which may be substituted, W Y may be substituted Good C 1-15 represents an alkylene group, etc., X Y represents 0, CH, NR 11Y, etc. D Y represents Q Y — Y — B Y, etc. Q Y represents X
  • Y When Y is NR 11Y , it represents a single bond or —CO 2, Y Y represents — (CR 18Y R 19Y )-m3Y, etc., and R 18Y and R 19Y each independently represents a hydrogen atom or a substituted atom. represents also good number 1-15 alkyl group such as carbon, M3Y represents Less than six, B Y is - represents NR 25Y R 26Y etc. , R 25Y , R 26Y are a hydrogen atom when X Y is not CH, an optionally substituted carbon number 1 to
  • nlZ, n2Z, n3Z represents 0 to 3
  • R 1Z , R 2Z , R 3Z , R 4Z , R 5Z , R 6Z are each independently a hydrogen atom or an optionally substituted carbon number. 1 to 15 alkyl group and the like, and R 5Z and R 6Z may form a carbonyl group together with the carbon atoms to which A 1Z and A 2Z are independently substituted, Furthermore, it represents a monocyclic or polycyclic heteroaromatic ring, etc.
  • W z represents an optionally substituted benzene ring, etc.
  • X z represents 0, CH, NR 11Z, etc.
  • D Z represents — Q Z — Y Z — B Z etc.
  • Q Z represents a single bond in the case of X Z force SCH, — C
  • ⁇ -, - CONH-, represent NR 12Z like
  • Y Z is - (CR 18Z R 19Z) - or the like represents, R 18Z, m3Z
  • R 19Z each independently represents a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, m3Z represents 0 to 6, B z represents —NR 25Z R 26Z or the like, R 25Z , R 26 z, if not X z force SCH is hydrogen atom, a substitutable number of 1 to 15 alkyl group carbon atoms which may have such
  • a pharmaceutically acceptable salt thereof, or a prodrug thereof is disclosed to have CX CR4 antagonistic activity (see WO 2005Z085209 pamphlet).
  • a 1V and A 2V each independently represent a group containing a basic group
  • B 1V and B 2V each independently represent a bond having 1 to 4 atoms of a bond or a main chain.
  • E v represents a spacer with 1 to 10 atoms in the main chain
  • L represents a spacer with 1 to 4 atoms in the bond or main chain;
  • J w Are (1) an aliphatic hydrocarbon group that is substituted by a group containing a basic group and may further have a substituent, and (2) is substituted by a group containing a basic group.
  • a spirocyclic group which may be substituted by a group containing a basic group or may further have a substituent
  • a base It represents a crosslinked cyclic group which may be substituted by a group containing a functional group or may further have a substituent, and the definition of each group is only necessary. Excerpt was.
  • Patent Document 1 International Publication No. 2003Z029218 Pamphlet
  • Patent Document 2 International Publication No. 2004Z024697 Pamphlet
  • Patent Document 3 International Publication No. 2005Z085209 Pamphlet
  • Patent Document 4 Pamphlet of International Publication No. 2006Z022454
  • Immune diseases eg, rheumatoid arthritis, arthritis, systemic lupus erythematosus, retinopathy, macular degeneration, pulmonary fibrosis, transplanted organ rejection
  • allergic diseases infectious diseases (eg, human immunodeficiency) Virus infection, acquired immune deficiency syndrome, etc.)
  • cancer disease eg, cancer, cancer metastasis, etc.
  • heart vascular disease (eg, arteriosclerosis, myocardial infarction, angina, cerebral infarction, chronic arterial obstruction)
  • vascular disease eg, arteriosclerosis, myocardial infarction, angina, cerebral infarction, chronic arterial obstruction
  • Other preventive and Z or therapeutic agents, or regenerative medicine agents are useful as pharmaceuticals, and development of safe CXCR4 antagonists with few side effects is eagerly desired.
  • the present invention provides:
  • M A1 and M A2 each independently represents a group containing an acidic group which may be protected by a protecting group, and A 1 and A 2 each independently contains a basic group.
  • B 1 and B 2 each independently represent a bond or a spacer having 1 to 4 atoms in the main chain;
  • E is a spacer having 1 to 10 atoms in the main chain;
  • L represents a bond or a spacer having 1 to 4 atoms in the main chain;
  • J is (1) substituted by a group containing a basic group and further having a substituent.
  • An aliphatic hydrocarbon group that may be substituted (2) a monocyclic or condensed cyclic group that is substituted by a group containing a basic group and may further have a substituent, and (3) a basic group It may be substituted by a contained group or may have further substituents!
  • / May be a spiro-bound cyclic group, or (4) a basic group May be substituted by a group to be contained, may further have a substituent, and may represent a crosslinked cyclic group;
  • G represents a bond, a carbon that may have a substituent Atom, oxygen atom, optionally substituted nitrogen atom, optionally oxidized sulfur atom, or (optionally substituted carbon atom) (optionally substituted)
  • Pi and p 2 each independently represents 0 or 1. However, the sum of pi and p2 is 1 or more.)
  • M A1 and M A2 are each independently a group containing an acidic group protected by a protecting group, a salt thereof, an N-aged oxide, or a solvate thereof. Products, or prodrugs thereof;
  • Y 1 represents a methylene group which may have 1 to 2 substituents, an etylene group, an ethylene group which may have 1 to 2 substituents, a C ( O) —, 1 ⁇ , 1 S, 1 S (O) 1 or —SO—;
  • Y 2 and Y 3 are each independently a bond, 1-2
  • a methylene group 1 to 2 substituents, an ethylene group, an ethylene group, one C (O) —, one O , 1 S—, 1 S (O) —, or 1 SO—
  • Z A is (1) a carboxyl group which may be protected by a protecting group, (2) protected by a protecting group, may be a sulfo group, or (3) protected by a protecting group! Or a phosphono group;
  • ring D has a substituent! /, Or a monocyclic group;
  • q represents an integer of 1 to 6;
  • n and m each represent Independently represents 0 or an integer from 1 to 4.
  • q represents an integer of 2 or more
  • multiple Y 1 may be the same or different.
  • n represents an integer of 2 or more
  • multiple Y 2 may be the same or different.
  • multiple Y 3 may be the same or different.
  • the sum of n and m is 4 or less.
  • a 1 and A 2 are each independently a nitrogen-containing heterocyclic ring which may have a substituent, a salt thereof, an N-aged xide or a solvate thereof Or their prodrugs;
  • B 1 and B 2 are each independently —CO—, —SO—, or —CH—.
  • E is a divalent 3- to 8-membered monocyclic cyclic group which may have a substituent, or a divalent 9- to 10-membered condensed cyclic group which may have a substituent.
  • L A is — (an aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have a substituent)). An optionally substituted nitrogen atom), or a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms which may have a substituent,
  • L A is one of-(an aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have a substituent)-(a nitrogen atom which may have a substituent)
  • 1 is (3 to 10 monocyclic or bicyclic carbocyclic rings, or Represents a bicyclic heterocycle
  • L A is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms having substituents! /, 1 is at least one nitrogen atom. Further containing an oxygen atom and Z or oxidized, or a sulfur atom, which represents a 3- to 10-membered monocyclic or bicyclic heterocyclic ring,
  • a C3-10 mono- or bicyclic carbocycle substituted by a group containing a basic group (ii) a carbon atom, oxygen atom substituted by a group containing a basic group And Z or a sulfur nuclear which may be acidified is also a 3-10 membered mono- or bicyclic heterocycle, or (iii) at least one optionally substituted by a group containing a basic group It contains 3 nitrogen atoms, and further contains an oxygen atom or a sulfur atom which may be oxidized, and represents 3 to: a L0 membered monocyclic or bicyclic heterocyclic ring.
  • ring A lb and ring each independently represent an optionally substituted imidazole, benzimidazole, or pyridine ring;
  • B 1A and B 2A each independently represent CO— , -SO, or CH;
  • G 1 is CO-, -SO,
  • ring E 1 is a divalent 3- to 8-membered monocyclic ring which may have a substituent
  • L A represents the same meaning as in the above [15];
  • J 5 represents a basic group; May be substituted by a group containing, may further have a substituent, or may represent a spiro-bonded cyclic group;
  • Z 1A represents a carboxyl group which may be protected by a protecting group;
  • R 1Y and R 2Y each independently represent a hydrogen atom or a substituent;
  • rl represents an integer of 1 to 4;
  • the substituent in Z 1A is (1) absent, (2) an aminocarbonyl group substituted with a hydrocarbon group, or (3) an oxygen other than a carbon atom that may have a substituent.
  • R E represents a halogen atom, —o aliphatic hydrocarbon group, or aliphatic hydrocarbon group
  • t represents 0 or an integer of 1 to 2
  • two R E can be the same or different L B is CO CH co-co CO— CH
  • R 1 represents a hydrogen atom or a substituent.
  • R 1 is a C4-7 monocyclic carbocycle or a Cl-8 alkyl group, a salt thereof, an N-oxide or a solvate thereof, or a prodrug thereof; twenty two]
  • Z 1A is a carboxyl group which may be protected by an alkyl group of Cl to 8, a compound according to the above [20], a salt thereof, an N-oxide form or a solvate thereof, or a prodrug thereof drag;
  • a pharmaceutical composition comprising a compound represented by the general formula (I) according to the above [1], a salt thereof, an N-talide form or a solvate thereof, or a prodrug thereof;
  • CXCR4-mediated disease is human immunodeficiency virus infection, acquired immune deficiency syndrome, cancer, cancer metastasis, rheumatoid arthritis, arthritis, retinopathy, macular degeneration, pulmonary fibrosis, asthma, ischemic disease, systemic lupus erythematosus Or the pharmaceutical composition according to the above [26], wherein the force for transplantation organ rejection or the regenerative medicine is an agent for transplantation or mobilization of hematopoietic stem cells to the peripheral blood;
  • a pharmaceutical comprising a combination of one or more selected from interferons, biologics that perform T cell activity, and angiogenesis inhibitors;
  • the compound of the present invention has a CXCR4 antagonistic action, it is useful as a preventive and Z or therapeutic agent for diseases involving CXCR4, that is, CXCR4-mediated diseases.
  • the bond means that the bond is directly bonded without any other atom interposed therebetween.
  • examples of the “cyclic group” include a monocyclic or condensed cyclic group, a bridged cyclic group, and a spiro-bonded cyclic group.
  • the “monocyclic or condensed cyclic group” includes a monocyclic ring or a condensed carbocyclic ring, a monocyclic ring or a condensed heterocyclic ring.
  • examples of the “monocyclic or condensed carbocycle” include C3-15 monocyclic or condensed carbon rings.
  • the “C3-15 monocyclic or condensed carbocycle” includes a C3-15 monocyclic or unsaturated condensed carbocyclic ring, and a condensed carbon ring which is partially or entirely saturated.
  • Examples of the "C3-15 monocyclic or condensed unsaturated carbocyclic ring, a condensed carbocyclic ring partially or fully saturated” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, Tenene, cyclopentadiene, cyclohexadiene, cyclohexabutadiene
  • examples of the “C3-15 monocyclic or condensed aromatic carbocyclic ring” include benzene, azulene, naphthalene, phenanthrene, anthracene ring, etc.
  • the hetero atom includes 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms.
  • This “3- to 15-membered monocyclic or fused heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms” includes heterocycles.
  • 3 to 15 membered monocyclic or condensed unsaturated bicyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as atoms, part or all of them Includes heterocyclic rings that are saturated.
  • Examples of the ⁇ heterocycle partially or completely saturated '' include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, Thiopiran, Chepin, Oxazonole, Isoxazole, Thiazole, Isothiazole, Furazane, Oxadiazole, Oxazine, Oxazazine, Oxazepine, Oxadiazepine, Thiadiazonole, Thiazine, Thiadiazine, Thiazepine, Thiadiazepine, Indole, Iso
  • a 3- to 15-membered monocyclic or condensed aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophenone, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, thiadiazole, indole, isoindole, Benzofuran, Isobenzofuran, Benzothiene Fen, Isobenzothiphene Fen, Indazonore, Quinoline, Isoquinoline, Purine, Phthalazine, Pteridine, Naphthyridine, Quinoxaline, Quinazoline, Cinn
  • the “bridged cyclic group” includes a bridged carbocycle and a bridged heterocycle.
  • Examples of the “crosslinked carbocycle” include C4-15 crosslinked carbocycles.
  • Examples of 4 to 15 bridged carbocycles include bicyclo [2.2.1] heptane, bicyclo [2.2.1] hepter-2, bicyclo [3.1.1] heptane, bicyclo [3. 1. 1] Hepter 2 Cyan, Bicyclo [3. 2. 1] Octane, Bicyclo [2. 2. 2] Octane, Bicyclo [2.2.2] Octa 2—Chen, Adamantane, Nono Rare adamantane, bicyclo [2.1.1] hexane, bicyclo [3. 3.1] nonane, bicyclo [3.2.1] octane, bicyclo [3.3.2] decane ring.
  • the "bridged heterocycle” includes, for example, a bridged heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms. Is mentioned. “1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1 as heteroatoms “Bridged heterocycle containing 2 sulfur atoms” includes, for example, “1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 sulfur atoms as heteroatoms 4 ⁇ 15 membered bridged heterocycle ”.
  • examples of the “4- to 15-membered bridged heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms” include azabicyclo [ 2. 2. 1] Heptane, Oxabicyclo [2.2.1] Heptane, Azabicyclo [3.1.1] Heptane, Azabicyclo [3.2.1] Octane, Oxavici mouth [3.2.1] Octane, Azabicyclo [2.2.2] octane, diazabicyclo [2.2.2] otane, 1-azatricyclo [3. 3. 1. I 3 ' 7 ] decane, 3-azabicyclo [3. 3.1] nonane, 3, 7-diazabicyclo [3.3.1] nonane ring and the like.
  • “Spiro-bonded cyclic groups” include spiro-bonded carbocycles and spiro-bonded heterocycles.
  • examples of the “spiro-bonded carbocycle” include C7-15 spiro-bonded carbocycle.
  • Examples of the “C7-15 spiro-bonded carbocycle” include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, spiro [3.4] octane. And spiro [3.5] nonane ring.
  • spiro-bonded heterocycle examples include spiro-bonded heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms. It is done. 1 to 4 heteroatoms in this “spiro-bonded heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms” Spiro-bonded 7-15 membered heterocycles containing nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms.
  • a 7 to 15-membered spiro-bonded heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms as heteroatoms includes, for example, azaspiro [4. 4] Nonane, Oxazaspiro [4. 4] Nonane, Diazaspiro [4. 4] Nonane, Azaspiro [4. 5] Decane, Chiaspiro [4.5] Decane, Dithiaspiro [4.5] Decane, Dioxaspiro [4. 4. 5] Decane, Oxazaspiro [4.
  • decane 3 azaspiro [5.5] undecane, 2 azaspiro [5.5] undecane, 1 1 year old -4, 8 diazaspiro [5.5] undecane, 1 oxa 4, 9-Jazaspiro [5.5] Undecane, 3, 4-dihydrospiro [chromene 2, 4 'piperidine], 2 Fazaspiro [4.
  • examples of the “aliphatic hydrocarbon group” include a “linear or branched aliphatic hydrocarbon group”.
  • Examples of the “linear or branched aliphatic hydrocarbon group” include “an aliphatic hydrocarbon group having 1 to 8 carbon atoms” and the like, and “an aliphatic hydrocarbon group having 1 to 8 carbon atoms”.
  • Examples thereof include Cl-8 alkyl group, C2-8 alkyl group, C2-8 alkyl group and the like.
  • Examples of the Cl-8 alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl groups and isomers thereof.
  • Examples of the C2-8 alkenyl group include, for example, vinyl, propenyl, butenyl, pentenyl, hexenore, hepteninole, octenole, butageninore, pentageninore, hexaenyl, heptaenyl, octagenenyl, hexatrienyl. , Heptatrienyl, otatrienyl group and isomer groups thereof.
  • the C2-8 alkyl group includes, for example, ethul, probule, butyur, pentynyl, hexynyl, heptynyl, octynyl, butadinyl, pentadiynyl, hexazinyl, heptadinyl, octadinyl, hexatriynyl, heptatriynyl, Examples include otatriynyl groups and isomer groups thereof.
  • the “group containing a basic group” represented by A 1 and A 2 is not particularly limited as long as it contains a basic group.
  • a basic group (2) an aliphatic hydrocarbon group that may be substituted with a basic group, and further having a substituent, (3) a substituent with a basic group, and However, it may include a cyclic group.
  • aliphatic hydrocarbon group in the “aliphatic hydrocarbon group which is substituted by a basic group and may further have a substituent” has the same meaning as the above-described aliphatic hydrocarbon group.
  • cyclic group in the "cyclic group which may be substituted by a basic group and further have a substituent" has the same meaning as the above-described cyclic group.
  • C1-8 alkylidene group for example, methylidene, ethylidene, propylidene, butylidene
  • a cyclic group (4) an aliphatic hydrocarbon group substituted with a cyclic group (e.g., cyclopropylmethyl, cyclobenzylmethyl, cyclohexylmethyl, phenylmethyl, naphthylmethyl, pyridinylmethinole, cyclopropinoreethinole, cyclopentinoretinole, Cyclohexino retinore, feninoles chinore, naphthino retinore, pyridinino ethinore, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl, phenylmethyl, phenylpropyl, naphthinorepropyl, pyridylpropyl, etc.)
  • a cyclic group e.g., cyclopropylmethyl, cyclobenzylmethyl, cyclohexy
  • —O-aliphatic hydrocarbon group e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, propenyloxy, butenyloxy, pentenyloxy, hexyl
  • —O-cyclic group for example, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, phenoxy, naphthyloxy, pyridyloxy, etc.
  • —0-aliphatic hydrocarbon-cyclic group for example, cyclopentylmethoxy, cyclohexylmethoxy, benzinorexi
  • —S-aliphatic hydrocarbon monocyclic group for example, cyclopentylmethylthio, cyclohexylmethylthio, benzylthio, etc.
  • -S (0) monocyclic groups eg, cyclopropylsulfier, cyclopentylsulfininore, cyclohexenolesnorefi-nore, huenolesnorefi-nore, naphthinoresnorephinore, pyridine -Rustle field, etc.
  • O—CO aliphatic hydrocarbon group for example, acetyloxy, propionyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy, isobutanoyloxy, tert butanoyloxy, pentanooxy, hexanoyloxy , Heptanoyloxy, otatanoxy, propenooxy, butenooxy, pentenooxy, hexenooxy, propinooxy, butynoxy, pentinooxy, hexinooxy, etc.
  • (21) O—CO aliphatic hydrocarbon cyclic group (for example, cyclopentyl methanoyloxy, cyclohexyl methanoyloxy, phenol methanoyloxy, etc.),
  • (22) -CO-aliphatic hydrocarbon group e.g., acetyl, propionyl, propanoyl, isopropanoyl, butanol, isobutanol, tert-butanol, pentanoyl, hexanoyl, heptanoyl, otanoyl, propenoyl, butenoyl, pentenoyl, Hexenoles, propynols, butinoles, pentinoles, hexinoles, etc.),
  • (23) CO cyclic group for example, cyclopropyl carbonate, cyclopentyl carbo yl, cyclohexyl carbonyl, benzoyl, naphthyl carbonyl, pyridinyl carbonyl, etc.
  • CO aliphatic hydrocarbon monocyclic group eg, cyclopentyl methanol, cyclohexyl methanol, phenol methanol, etc.
  • Mono- or di-substituted amino group includes, for example, (0 substituted by aliphatic hydrocarbon group, GO cyclic group, GiO cyclic group)
  • Examples of the “mono- or di-substituted amino group” include, for example, methylamino, ethylamino, propylamino-containing isopropylamino-containing butylamino-containing isobutylamino-containing tert-butylamidopentylami-containing hexylamino-containing Heptylamino, octylamide, dimethylamine, dimethylamine, dipropylamine, dibutylamine, dipentylami, dihexylamino, diheptylami, dioctylamine, N-methyl-Nethylamine, cyclopropylami, cyclopentylami
  • Mono- or di-substituted sulfamoyl group includes, for example, (0 aliphatic hydrocarbon group, GO cyclic group, (iii) cyclic group) And substituted aliphatic hydrocarbon groups, etc.
  • Examples of the “mono- or di-substituted sulfamoyl group” include N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, N-isobutylsulfamoyl, N- (tert-butyl) sulfamoyl, N-pentylsulfamoyl, N-hexylsulfamoyl, N-heptylsulfamoyl, N-octylsulfamoyl, N , N Dimethylsulfamoyl, N, N— Jetylsulfamoyl, N, N Dipropylsulfamoyl, N, N—Dibu Rusulfamoyl, N, N dipentylsulfam
  • COO aliphatic hydrocarbon cyclic group for example, cyclopentylmethoxycarbon, cyclohexylmethoxycarbonyl, benzyloxycarbon, etc.
  • Mono- or di-substituted rubamoyl group (in this case, “substituent” in “mono- or di-substituted carbamoyl group” includes, for example, (0 aliphatic hydrocarbon group, GO cyclic group, Gii) cyclic group
  • Examples of the “mono- or di-substituted rubamoyl group” include, for example, N-methylcarbamoyl, N ethylcarbamoyl, N-propyl carbamoyl, N-isopropyl rubamoyl, N Butylcarbamoyl, N-isobutylcarbamoyl, N- (tert butyl) force rubamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, N-heptylcarbamoyl, N-octylcarbamoyl, N-cyclopropylforce
  • Aliphatic hydrocarbon group for example, acetylamino-containing propionylamino-containing isopropanolyl-containing butanoylami-containing isobutanol-containing tert-butanoylami-containing pentanoylami-containing heptanylami-containing heptanoylamino-containing octanoylamino, pro Pennoylamino buteneolami pentenolamine, hexenoluria, propionylami, butinoylami, pentinoylami, hexinoylamino, etc.),
  • a methyl group substituted with 1 to 3 halogen atoms eg, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, etc.
  • Methoxy groups substituted by 1 to 3 halogen atoms eg, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, etc.
  • substituents may be substituted at any substitutable position in any number of substitutable positions. Preferably, 1 to 8, more preferably 1 to 5 may be substituted.
  • the “aliphatic hydrocarbon group” and “cyclic group” in T each have the same meaning as described above.
  • “-aliphatic hydrocarbon mono” represents a divalent aliphatic hydrocarbon group, for example, a divalent group obtained by removing one arbitrary hydrogen atom from the “aliphatic hydrocarbon group”.
  • amino group For example, (a) amino group, (b) amidino group, (c) gua-dino group, (d) hydrazino group, (e) mono- or di-substituted amino group, (f) mono-, di- or A tri-substituted amidino group, (g) a mono-, di-, tri- or tetra-substituted gua-dino group, (h) a mono-, di- or tri-substituted hydrazino group, (i) V, nitrogen-containing heterocyclic group and the like.
  • Examples of the ⁇ convertible amino group '' include, for example, methylamino, ethylamino, propylamino-containing isopropylamino, butylamino, isobutylami-containing tert-butylami-containing pentylami-containing hexylamino-containing dimethylami-containing dimethylamino-containing dipropyl ami-di-dibutylamino, dipentylami-diated Xylamino, diheptylamino, dioctylamino, N-methyl-N-ethylamino-containing cyclopropylamino-containing cyclopentylami-containing cyclohexylami-containing diphenylamino-containing dibenzylamino, N-phenyl-N-methylamino-containing N-phenyl N-ethylamine-containing N N-methylamino N benzyloxy N ethylamine
  • Examples of the “substituent” in the “mono-, di- or tri-substituted amidino group” include (1) an aliphatic hydrocarbon group (having the same meaning as described above), (2) a cyclic group (having the same meaning as described above) And (3) an aliphatic hydrocarbon group substituted by a cyclic group (the aliphatic hydrocarbon group and the cyclic group have the same meaning as described above) and the like.
  • Examples of the ⁇ mono-, di- or tri-substituted amidino group '' include, for example, methylamidylated ethylamidylated propylamidylated isopropylamidino, butylamidino, isobutylamidylated tert butylamididated pentylamidylated hexylamidino, heptylamidino, octylamidided N, N Dimethylamidino, N, N 'Dimethylamidino, N, N, N' Trimethylamidino, N, N Jetylamidino, N, N 'Jetylamidino, N, N, N'-Triethylamidine N, N Dipropylamidine N, N' —With dipropylamid ⁇ , ⁇ , ⁇ '—Tripropylamid with ⁇ , ⁇ Dibutyl Amidino, N, N'-dibutylamidin
  • Examples of the “substituent” in the “mono-, di-, tri- or tetra-substituted gua-dino group” include (1) an aliphatic hydrocarbon group (having the same meaning as described above), (2) a cyclic group (and And (3) an aliphatic hydrocarbon group substituted with a cyclic group (the aliphatic hydrocarbon group and the cyclic group have the same meanings as described above).
  • Examples of the “mono-, di-, tri- or tetra-substituted tetra-substituted guanidino group” include, for example, methyl diamine diethyl didipropyl guanidinium isopropyl guanidinium butyl danidi diisobutyl anidiene tert-butyl dananidi dipentyl guanidinium Dino, hexylguanidino, heptyl ananidino, otatildananidi N, N-dimethyl dananino, N, ⁇ '-dimethyl dananidi ⁇ , ⁇ , ⁇ '-trimethyl dananidi ⁇ , ⁇ , ⁇ ', — "-tetramethyl ⁇ , ⁇ —Jechino Leguanizino, ⁇ , N'—Jechino Leguanizino, ⁇ , ⁇ , N'—Tretino Leguanji ⁇
  • Examples of the “substituent” in the “mono-, di- or tri-substituted hydrazino group” include (1) an aliphatic hydrocarbon group (having the same meaning as described above), and (2) a cyclic group (having the same meaning as described above). And (3) an aliphatic hydrocarbon group substituted by a cyclic group (the aliphatic hydrocarbon group and the cyclic group have the same meaning as described above) and the like.
  • Examples of the “mono-, di- or tri-substituted hydrazino group” include, for example, methyl hydrazine-containing ethyl hydrazide-containing propyl hydrazide-containing iso-propyl hydrazino, butyl hydrazino, isobutyl hydrazino, tert-butyl hydrazino, pentyl hydrazino, hexyl hydrazino , Heptyl hydrazino, octyl hydrazino, N, N-dimethyl hydrazide N, N'-dimethyl hydrazide N, N, N'-trimethyl hydrazide N, N-jetyl hydrazide N, N'-jetyl hydrazide With N, N, N'-triethyl hydrazide with N, N-dipropyl hydrazi with N, N'-di
  • Nitrogen-containing heterocycle in “having a substituent! /, May-! /, Nitrogen-containing heterocycle” means a 3 to 15-membered monocyclic or condensed ring having at least one nitrogen atom
  • Heterocycles, bridged complex rings, spiro-linked heterocycles include, for example, pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, oxazole, thiazole, isoxazole, isothiazole , Indole, isoindole, quinoline, isoquinoline, benzoxazole, benzothiazole, benzimidazole, aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thionophorin, perhydroazepine, perhydrodiazepine , Indoline
  • the "substituent" in the "nitrogen-containing heterocycle which may have a substituent” includes, in addition to the substituent exemplified as the T, (a) (5) in the T To (26), (29) to (32), and (37) to (55), an aliphatic hydrocarbon group substituted by 1 to 5 substituents (the aliphatic hydrocarbon group is And (b) 1 to 5 substituents selected from (5) to (26), (29) to (32), and (37) to (55) in T (The cyclic group has the same meaning as described above), (c) (5) to (26), (29) to (32), and (37) to (55) in T An aliphatic hydrocarbon group substituted by a cyclic group substituted with 1 to 5 substituents whose force is also selected (the cyclic group and the aliphatic hydrocarbon group have the same meaning as described above). . These optional substituents may be substituted at any substitutable position by any number that can be substituted. Preferably, 1 to 8, more
  • pi and p2 each independently represent 0 or 1.
  • the "group containing an acidic group" of the "group protected by an protecting group, which may be protected by a protecting group” represented by M A1 and M A2 is an acidic group. It is not particularly limited as long as it is included.
  • an acidic group (2) an aliphatic hydrocarbon group that may be substituted by an acidic group, and (3) an acidic group that further has a substituent.
  • a cyclic group (4) the “aliphatic hydrocarbon group which is substituted by an acidic group and may further have a substituent” described in the above (2), and further has a substituent.
  • aliphatic hydrocarbon group substituted by an acidic group and further having a substituent "an aliphatic hydrocarbon group substituted by an acidic group and further having a substituent"
  • a cyclic group optionally having a substituent “ substituted by an acidic group, and further having a substituent, further substituted by a cyclic group and further having a substituent.
  • an optionally substituted aliphatic hydrocarbon group ”, and“ V substituted with an acidic group and further having a substituent, further substituted with an aliphatic hydrocarbon group and further having a substituent “a cyclic group optionally having a substituent”
  • the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group substituted by a cyclic group” may be the above-described aliphatic hydrocarbon group.
  • Any carbon atom in the chain carbon atoms Oxygen atom, sulfur atom, phosphorus atom and Z or nitrogen atom which may have a substituent (the substituent here is the substituent etc. exemplified as the above-mentioned T) Represents a group substituted with a).
  • These optional carbon atoms have 1 to 3 oxygen atoms, sulfur atoms, phosphorus atoms and Z or substituents at substitutable positions, but may be substituted with nitrogen atoms.
  • Cyclic group substituted by an acidic group and further having a substituent "Aliphatic hydrocarbon group substituted by an acidic group and may further have a substituent A cyclic group optionally having a substituent substituted by ",” substituted with an acidic group and further having a substituent, or even substituted by a cyclic group and further having a substituent. However, it may be substituted with an aliphatic hydrocarbon group that is substituted with an aliphatic hydrocarbon group that may be substituted with an aliphatic group that may be further substituted.
  • the “cyclic group” in the “aliphatic hydrocarbon group optionally substituted by a substituted with a good cyclic group” has the same meaning as the aforementioned cyclic group.
  • Cyclic group substituted with an acidic group and further having a substituent "Cyclic group optionally substituted with an acidic group and further substituted”
  • substituent in the “substituted aliphatic hydrocarbon group optionally having a substituent, further substituted by a cyclic group, and further having a substituent”
  • examples of the “acidic group” include the following first group and second group.
  • a hydroxysulfonylamino group (one NR 1C) 1 SO H (R 1C) 1 is a hydrogen atom or a substituent
  • ⁇ 2nd group> A phenolic hydroxyl group (1 C H OH), or a hydrogen atom that can be deprotonated.
  • “Bronsted acid” in “various prested acids such as nitrogen-containing ring residues having a hydrogen atom capable of deprotonation” refers to a substance that gives hydrogen ions to other substances. Indicates.
  • nitrogen-containing ring residue having a hydrogen atom that can be deprotonated” in “various Brenstead acids such as nitrogen-containing ring residue having a deprotonated hydrogen atom” include, for example,
  • the “protecting group” of the “group containing an acidic group” represented by M A1 and M A2 may be a group containing an acidic group. If it protects, it will not specifically limit.
  • the protecting group for the group containing an acidic group shown in the first group include a hydrocarbon group which may have a substituent, an amino group which may have a substituent, Cl to 6
  • the protecting group for the group containing an acidic group shown in the second group include hydrocarbon groups that may have a substituent. Groups and the like. However, in the case where the acidic group is a phosphono group and two hydrogen atoms of the phosphono group have a substituent, and are protected by a hydrocarbon group, they have two substituents.
  • the hydrocarbon group may be taken together to represent a C2-4 alkylene group.
  • a P represents an oxygen atom or an optionally substituted nitrogen atom, represents a ring or a cyclic group that may further have a substituent
  • D P and E P each independently represent: Replace May be a C1-8 alkylene group, substituted !, may be a C2 to 87 alkylene group, an optionally substituted C2 to 8 alkylene group or a bond
  • M P represents a spacer or bond containing an oxygen atom, nitrogen atom, sulfur atom and Z or phosphorus atom in the main chain
  • R P represents a hydrogen atom or a substituent
  • mp represents an integer of 1 to 3.
  • np represents an integer of 0 or 1
  • np is more ring B P when 2 May be the same or different.
  • the “hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentinole, hexyl, heptyl, octinole, noninore, decinole, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and the like Cl-15 alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc.
  • cycloalkyl groups such as bur, allyl, 2-methylallyl, 2-butyr, 3-butenyl, 3-octatur, etc.
  • C2-10 alkenyl groups such as echtur, 2-propyl, 3- C2-10 alkyl groups such as hexyl groups, for example C3-10 such as cyclopropyl, cyclopentale, cyclohexenyl groups, etc.
  • Cycloalkenyl groups such as C6-14 aryl groups such as phenol and naphthyl groups, C7-16 aralkyl groups such as benzyl and phenyl groups, such as cyclohexylmethyl, cyclohexylethyl, and cyclohexyl.
  • substituents in the “hydrocarbon group optionally having substituent (s)” include (1) nitro group, (2) hydroxyl group, (3) oxo group, (4) thixo group, ( 5) Ciano group, (6) Carbamoyl group, (7) N-Butylaminocarbol group, N-cyclohexylmethylaminocarbonyl, N-butyl-N-cyclohexylmethylaminocarbonyl, N-cyclo Hexylaminocarbol, phenaminocarbol group and the like substituted with Cl-8 hydrocarbons, (8) carboxyl group, (9) eg methoxycarbol, ethoxycarbol Cl ⁇ 4 alkoxy carbo group such as ru group, (10) s
  • a lower alkyl sulfo group of Cl to 4 such as methylsulfol, ethylsulfol group, etc.
  • Substituted by Cl to 4 lower acyl group such as mil, acetyl group, (20) benzoyl group, (21) (a) halogen atom such as bromine atom, chlorine atom, fluorine atom, (b) oxo group, hydroxy group, etc.
  • a hydrocarbon group such as methinole, ethynole, propyl, isopropyl, benzyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl group
  • this ⁇ hydrocarbon group '' is the above-mentioned ⁇ hydrocarbon group '' And (c)
  • o-, m- or p black mouth phenoxy group, o-, m- or p, halognophenoxy group such as bromophenoxy, and (d) oxo group, etc.
  • substituents e.g.
  • the “hydrocarbon group which may have a substituent” is selected from the forces (1) to (22) in the “substituent” of the “hydrocarbon group which may have a substituent”. Even if it has 1 to 10 substituents, the “hydrocarbon group” is preferably a cycloalkyl, cycloalkenyl, aryl or aralkyl group. In this case, for example, 1 to 4 lower alkyl groups of Cl to 4 such as methyl, ethyl, propyl, isopropyl, butyl and the like may be substituted. When the number of substituents is 2 or more, each substituent may be the same or different.
  • the “substituent” of the amino group in the “amino group optionally having substituent (s)” is the above-mentioned “hydrocarbon group optionally having substituent (s)”. And the like.
  • examples of the “C1-6 alkoxy group” include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups and the like.
  • examples of the “cyclic group” in the “cyclic group optionally having substituent (s)” represented by ring B P include, for example, “carbocycle”, “heterocycle”, or “ Examples thereof include a divalent group obtained by removing any two hydrogen atoms from a “steroid skeleton” or the like.
  • Examples of the "carbocycle” as the "cyclic group” in the “cyclic group optionally having substituent (s)" represented by ring B P include “C3-15 carbocycle” and the like. It is done. “C3-15 carbon ring” includes “C3-15 monocyclic, bicyclic or tricyclic carbocycle” and “C3-15 spiro-bonded bicyclic carbocycle and bridged bicyclic carbon. Ring “and the like.
  • Examples of the ⁇ C3-15 monocyclic, bicyclic or tricyclic carbocycle '' include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclo Dodecane, Cyclotridodecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclooctene, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclooctagen, Benzene, Pentalene, Perhydropentalene , Azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydron
  • C3-15 spiro-bonded bicyclic carbocycles and bridged bicyclic carbocycles include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] Ndecane, bicyclo [2. 2. 1] heptane, bicyclo [2. 2. 1] hepter 2-ene, bicyclo [3. 1. 1] heptane, bicyclo [3. 1. 1] hepter 2-en Bicyclo [3. 2. 1] Octane , Bicyclo [2.2.2] octane, bicyclo [2.2.2] octa-2-ene, adamantane and noradamantane ring.
  • Examples of the "heterocycle” as the "cyclic group” in the “cyclic group optionally having substituent (s)" represented by ring B P include, for example, "1 to 5 nitrogen atoms, 1 to 3 to 15-membered heterocycle containing 2 oxygen atoms and Z or 1 sulfur atom ”.
  • “3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes “1 to 5 nitrogen atoms, 1 to 2 3-15 membered monocyclic, bicyclic or tricyclic heterocycle containing 1 oxygen atom and Z or 1 sulfur atom "and" 1-5 nitrogen atom, 1-2 oxygen atom and Z Or a 3 to 15-membered spiro-linked bicyclic heterocycle and a bridged bicyclic heterocycle containing one sulfur atom.
  • Decane 1, 4, 9- Triazaspiro [5.5] Undecane, Oxazaspiro [4.5] Decane, Azaspiro [5.5] Undecane, Azabicyclo [2. 2. 1] Heptane, azabicyclo [3. 1. 1] heptane, azabicyclo [3.2.1] octane (8-azabicyclo [3.2.1] octane ring, etc.), azabicyclo [2.2.2] Octane (2-azabicyclo [2.2.2] octane ring, etc.), azabicyclo [2.1.1] hexane (5-azabicyclo [2.1.1] hexane ring Etc.) Ring etc. are mentioned.
  • the "steroid skeleton" in the "steroid skeleton optionally having a substituent” represented by ring B P is any as long as it is generally referred to as a steroid skeleton. Usually, it may be a perhydro-1H-cyclopenta [a] phenanthrene skeleton.
  • the "steroid skeleton may have a substituent", for example, cholic acid represented by the formula (S P), Dokishikoru acid, Quai Node O carboxymethyl cholate, Urusokoru acid is derived from Urusodokishiko one Le acid structure Is mentioned. [Chemical 17]
  • R 1AP -OH: Cholic acid
  • R 1AP H
  • R p a -OH: Deoxycholic acid
  • R 1AP a -OH.
  • R 2 * ⁇ H Kenodeoxycholic acid
  • R 1AP ⁇ - ⁇
  • R 2AP H: Ursodeoxycholic acid
  • the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring BP is not particularly limited as long as it is a substituent.
  • substituent for example, (1) substituted or C1-20 alkyl group, (2) substituted !, C2-20 alkyl group, (3 ) An optionally substituted C2-20 alkyl group, (4) an optionally substituted Cl-20 alkylidene group, (5) an optionally substituted cyclic group, (6) an oxo group, ( 7) Hydroxyl group, (8) optionally substituted Cl-20 alkyloxy group, (9) optionally substituted V, C2-20 alkoxy group, (10) substituted!
  • C2-20 alkyloxy group (11) hydroxyl group optionally protected by an optionally substituted cyclic group, (12) optionally substituted Cl-20 acyloxy group, (13) thixo Group, (14) mercapto group, (15) substituted !, may be C1-20 alkylthio group, (16) substituted !, may be C2-20 alkyl thio group, (17) Optionally substituted C2-20 Alkylthio group, (18) substituted, or mercapto group substituted with a cyclic group, (19) substituted !,!
  • Cl-20 alkylsulfier groups eg, methylsulfiyl groups) -Group, ethylsulfinyl group, etc.
  • a sulfiel group substituted with a cyclic group for example, a fullsulfuryl group
  • an optionally substituted Cl-20 alkylsulfol group for example, a methylsulfol group, an ethylsulfol group) -Group
  • an optionally substituted C2-20 alkenylsulfol group, ( 25) substituted ! may be C2-20 alkynylsulfol groups
  • sulfo groups substituted with cyclic groups that may be substituted eg, phenylsulfonyl groups, etc.
  • an optionally substituted sulfino group 28) an optionally substituted sulfo group
  • an optionally substituted sulfamoyl group eg, an unsubstituted sulfamoyl group, N-mono Or di (optionally substituted Cl-20 alkyl) sulf
  • “substituted” in the “substituent” in (29), (32), (34), and (38) of “an optionally substituted cyclic group” represented by ring B P And may be a sulfamoyl group "," substituted and may be rubamoyl group "," substituted and may be amidino group "and” substituted and may be an amino group " Is a 5- to 7-membered group containing 1 to 5 nitrogen atoms, 1 oxygen atom and Z or 1 sulfur atom, together with the nitrogen atom to which they are attached when there are 2 substituents
  • This heterocycle which may be a monocyclic heterocycle, may be substituted by a Cl-8 alkyl group, a hydroxyl group or an amino group! /.
  • cyclic group has the same meaning as “cyclic group” in the ring.
  • substituents for ring B P the description “optionally substituted” means that they may be substituted by substituents.
  • substituents for example, (1) C1-20 anorequinole group, (2) C2-20 anoreke-nore group, (3) C2-20 alkynyl group, (4) C1-20 alkylidene group, (5) cyclic group, (6) C1-20 alkyl group substituted with cyclic group, (7) oxo group, (8) hydroxyl group, (9) C1-20 alkyloxy group, (10) C2-20 alkoxyloxy Group (11) C2-20 alkyloxy group, (12) hydroxyl group optionally protected by a cyclic group, (13) C1-20 acyloxy group, (14) thixo group, (15) mercapto group, ( 16) C1-20 alkylthio group, (17) C2-20 alkylthio group, (18) C2-20 alky
  • C1-20 alkyl group means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Noel, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl Hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl groups and their isomer groups.
  • C2-20 alkyl group refers to ethyl, probe, butur, pentul, hexyl, heptul, otatur, nonel, decel, It means undecyl, dodecyl, tridecenyl, tetradecyl, pentadecyl, hexadecyl, heptadecenyl, octadecenyl, nonadecenyl, icosyl groups and their isomeric groups.
  • C2-20 alkyl group means ethynyl, propiel, butur, pentyninole, hexchnore, hept-nore, octinore, no-nore, decinore, It means undecynole, dodecyl, tridecynyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecynyl, icosinyl and their isomeric groups.
  • C1-20 alkylidene group means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, otatilidene, no-lidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentade It means a silidene, hexadecylidene, heptadecylidene, octadecidylidene, nonadecylidene, icosilidene group and isomer groups thereof.
  • C1-20 alkyloxy group means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, Pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy groups and their isomeric groups means.
  • C2-20 alkoxy group refers to ethuroxy, propoxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, none-loxy, dece-loxy, undec It means -loxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecenyloxy, heptadecyloxy, octadecyloxy, nonadeceroxy, icocenyloxy and their isomeric groups.
  • C2-20 alkyloxy group refers to ethuroxy, propoxy, butynyloxy, pentynyloxy, hexyloxy, heptynyloxy, octyloxy, nitro-oxy, decoxyloxy.
  • C1-20 alkylthio group means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecyl It means ruthio, pentadecylthio, hexadecylthio, heptadecylthio, octadecylthio, nonadecylthio, icosylthio groups and isomer groups thereof.
  • C2-20 alkthio group refers to ethenylthio, probethio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonethio, decthio , Undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecenylthio, hexadecenylthio, heptadecylthio, octadecenylthio, nonadecenylthio, icosenylthio and their isomeric groups means.
  • C2-20 alkylthio group means ethylthio, propylthio, butynylthio, pentynylthio, hexylthio, heptynylthio, octynylthio, no-- Lucio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadesur Thio, octadecyrylthio, nonadecylthio, icosylthio and their heterologous groups.
  • C1-20 alkyl sulfier group means methyl sulfier, ethyl snorefi-nore, propinoles norefi-nore, butinoles norefi-nore, pentinores norefi -Nore, Hexinoles Norefi-Nore, Heptinoles Norefi-Nore, Otacinores Norefi-Nore, Noninoles Norefirl, Decyl Sulfiel, Undecyl Sulfiel, Dodecyl Sulfiel, Tridecyl Means sulfiel, tetradecylsulfur, pentadecylsulfyl, hexadecylsulfinyl, heptadecylsulfuryl, octadecylsulfuryl, nonadecylsulf
  • C2-20 alkenylsulfier group means etulsulfier, propenonolesnorefininore, buteninoresnorefininore, penteninoresnorefininore, hexenoresnorefininore, Hepteninolesnorefininole, otateninoresnorefininore, noneninoresnorefinil, decenylsulfier, undecenylsulfier, dodecenylsulfier, tridecenylsulfuryl, tetradecenyls Lufyl, pentadecenylsulfuryl, hexadecenylsulfuryl, heptadecenylsulfuryl, octadecenylsulfuryl, nonadecylsulfil, icocenylsulf
  • C2-20 alkylsulfier group refers to ethylsulfier, propyninoresnorefininore, butininoresnorefininore, pentinoinoresnorefininore, hexnoresnorephinore, Heptyl Noles Nore, Otachi Noles Nore Nore, Non-Ninoles Nore, Decyl Sulfyl, Undecyl Sulfyl, Dodecyl Sulfyl, Tridecyl Sulfyl, Tetradecyl Rusulfil, It means pentadesulfuryl, hexadecylsulfil, heptadesulfuryl, octadecylsulfil, nonadecylsulfuryl, icosinylsulfiel groups and their isomeric groups.
  • C1-20 alkylsulfol group means methylsulfol, ethyls norehoninole, propinolesnorehoninore, butinolesnorehoninore, pentinoresnorehoninore, Chinore Sunorehoninore, Heptinolesnorehoninore, Okutinoresnorehoninore, Noninoresnorehoninore.
  • C2-20 alkenylsulfol group means etulylsulfol, propenolesnorenore, buteresnorenore, pentenorenorenoninore, hexe- Noresnorejo Ninore, Hefteninoresnorehoninore, Taittenenoresnorehoninore, Nono Ninoresnorehoninore, Ninoreno, Undesenorejo-nore, Dodesenorenorenore, Toridese Nolesnoleol, tetradecylsulfol, pentadecenylsulfol, hexadecylsulfol, heptadecenylsulfol, octadecylsulfol, nonadecylsulfol, icocenylsulfur and These
  • C2-20 alkylsulfol group means ethylsulfol, propyninoresnorehoninore, butyninoresnorehoninore, pentyninoresnorehoninore, hexyl Ninoles Nore Ninore, Heptininoles Norehoninore, Tasty Kuchininores Norehoninore, Nonininores Norehoninole, Tenninore Sunorehoninore, Undesi-Noresnorejo-Nole, Dodeci-Nolesnore-Honore Meaning sulfosulfol, pentadecylsulfol, hexadecylsulfol, heptadecylsulfol, octadecylsulfol, nonadecylsulfol, icos
  • the "C1-20 acyl group” means methanol, ethanol, propanoyl, butanol, pentanoyl, hexanoyl, heptanoyl, otatanyl, nonanoyl, decanol, undecanol, tetradecanol, tetradecanol, tridecanol, Hexadecanol, heptadecanol, octadecanol, nonadecanol, icosanol and their isomers.
  • the “C1-20 acyloxy group” means methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanooxy, hexanoyloxy, heptanoyloxy, otanooxy, nonanoyloxy, decanoxy, decanoxy Undeoxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy, pentadecanoyloxy, hexadecanoyloxy, heptadecanoyloxy, heptadecanoyloxy, octadeca Nyloxy, nonadecanoxy, icosanoyloxy groups and isomers thereof are meant.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the "optionally substituted nitrogen atom” represented by A P means "the spacer having 1 to 4 atoms in the main chain” represented by the following and B 2 . Even if it has a substituent, it represents the same meaning as “a divalent nitrogen atom”.
  • the "optionally substituted Cl-8 alkylene group" represented by D P and E P is an arbitrary substituent bonded to any carbon atom of the Cl-8 alkylene group. It means what you did.
  • Examples of such a “substituent” include the substituents exemplified above as the “substituent” in the “cyclic group” which may further have a substituent represented by ring BP . It is
  • the "optionally substituted C2-87 alkylene group" represented by D P and E P means any carbon atom of the C2-87 alkylene group, and any This means that the substituent is bonded.
  • substituents include the substituents exemplified above as the “substituent” in the “cyclic group” which may further have a substituent represented by ring BP . It is done.
  • the "optionally substituted C2-8 alkylene group" represented by D P and E P is any carbon atom of the C2-8 alkylene group. This means that the substituent is bonded.
  • substituents include the substituents exemplified above as the “substituent” in the “cyclic group” which may further have a substituent represented by ring BP . It is done.
  • a spacer including an oxygen atom, a nitrogen atom, a sulfur atom and a Z or phosphorus atom in the main chain represented by M P means an oxygen atom or a nitrogen atom in the main chain. Represents a spacer containing at least one sulfur atom and / or phosphorus atom, and the type and number of other constituent atoms are not limited.
  • spacers that contain oxygen, nitrogen, sulfur and / or phosphorus atoms in the main chain include: —COO—, —COOCO—, 1 CONR XP —, 1 CONR XP CO—, 1 O —, One OCO—, One OCOO—, One OCON - one - one NR XP CO - one NR XP COO - one NR ⁇ CONR -, One S -, - S (O) -, -SO one, -SO -, -NR XP SO one, OSO- And OP (
  • R ZP 0
  • R XP and R YP each independently represent a hydrogen atom or a substituent, and R ZP represents an optionally protected hydroxyl group or “0_”.
  • the “substituent” represented by R P , R XP and R YP is not particularly limited as long as it is a substituent.
  • examples of the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B P include the substituents exemplified above.
  • examples of the “protecting” group in the “optionally protected hydroxyl group” represented by R ZP include, for example, “having a substituent further represented by ring BP.
  • examples of the “substituent” in the “optional cyclic group” include the same as those exemplified above.
  • R ZP represents an oxygen ion
  • a cation part eg, quaternized, for example
  • Nitrogen atoms, etc. are present.
  • C 1-8 alkylene group means, for example, methylene, ethylene, trimethylene
  • Tetramethylene pentamethylene, hexamethylene, heptamethylene, otatamethylene group and isomer groups thereof.
  • C 2 -87 lucerene group refers to, for example, etylene, proberene, butenylene, butagenylene, pentylene, pentagenylene, hexenylene, hexadiene, and the like. , Hepterene, heptajylene, otaterene, octagelenene group and isomer groups thereof.
  • C2-8 alkylene group means, for example, ethylene, propylene, butynylene, butazinylene, pentylene, pentaziylene, hexynylene, hexazilene.
  • the group represented by the general formula (P) is:
  • the "group containing an acidic group” in the "group containing an acidic group protected by a protecting group” represented by M A1 and M A2 means the above-mentioned "containing an acidic group” The meaning is the same as “group”.
  • the “protecting group” in the “group containing an acidic group protected by a protecting group” represented by M A1 and M A2 has the same meaning as the above-mentioned “protecting group”.
  • prodrugated in the “group containing a prodrug acid group” means the solubility of the compound, gastrointestinal mucosa permeability, blood permeability, tissue
  • the structure has been chemically modified for the purpose of improving the bioavailability as a drug, improving the bioavailability as a drug, or improving the properties that cause problems during oral administration, such as the bitterness and irritation of the compound. means.
  • group containing a prodrug-containing acidic group refers to a reaction in the living body with an enzyme such as hydrolase or oxidoreductase, gastric acid, or the like, or physiological Any structure may be used as long as the structure is converted into the original “group containing an acidic group” under the conditions.
  • groups containing an acidic group protected by a protecting group represented by M A1 and M A2 described above.
  • a carboxyl group optionally protected by a protecting group "a sulfo group optionally protected by a protecting group” represented by ⁇ ⁇ ⁇ ⁇ , and “protected by a protecting group;
  • the “protecting group” of the “phosphono group” is the “protecting group” of the “group containing an acidic group that may be protected by a protecting group” represented by ⁇ ⁇ 1 and ⁇ ⁇ 2 .
  • protecting carboxyl group which may be protected by a group represented by Z 1A is protected by a "protecting group represented by Z A and! ⁇ I be! / ⁇ carboxyl This means the same as “group”.
  • hydrocarbon group protected by an optionally substituted hydrocarbon group represented by z 1A ! May be a carboxyl group
  • the “hydrocarbon” in the “aminocarbonyl group substituted with a group” has the same meaning as the “hydrocarbon group” in the “hydrocarbon group”.
  • oxygen atoms, sulfur atoms, and 5- or 6-membered heterocyclic groups containing 1 to 4 heteroatoms selected from Z or nitrogen atoms Examples of the ⁇ 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, and Z or nitrogen nuclear energy '' include pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, Oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, thiadiazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline Triazolidine, tetrazoline
  • substituted examples include, for example, the “substituent” in the definition of “optionally substituted” in the substituents exemplified in (1) to (44) as the substituent of ring BP. Substituents There be mentioned up. As used herein, the “substituent” may be the same or different when there are two or more substituents that may be substituted at 1 to 4 substitutable positions.
  • C1-8 alkyl group in the "carboxyl group optionally protected by a C1-8 alkyl group” represented by Z 1A is the above "aliphatic hydrocarbon group”. It represents the same meaning as “C1-8 alkyl group”.
  • substituted represented by R 1Y and R 2Y is not particularly limited.
  • the substituents exemplified as the T may be mentioned, and these optional substituents may be substituted at one or two substitutable positions.
  • ring A 1B and ring A 2B is an imi which may have a substituent. It represents dazole, benzoimidazole which may have a substituent, or pyridine which may have a substituent.
  • the "substituent" in the “optionally substituted imidazole, benzimidazole, or pyridine” represented by ring A 1B and ring A 2B is the above-mentioned A 1 and in a 2 "have a substituent, also, nitrogen-containing heterocycle” represents the same meaning as the "substituent" in.
  • a spacer having 1 to 4 atoms in the main chain represented by B 1 and B 2 means an interval in which up to 4 nuclear atoms in the main chain are connected.
  • the “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • the number of 1,2-cyclopentylene atoms is 2, and the number of 1,3-cyclopentylene atoms is 3.
  • “Number of atoms in the main chain Examples of 1 to 4 spacers include 1 O, 1 S, 1 CO—, -SO-, -SO-
  • a divalent nitrogen atom which may have a substituent a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms which may have a substituent, and a divalent carbon atom which may have a substituent.
  • Examples thereof include a divalent group consisting of 1 to 4 arbitrarily selected from a valent 3- to 8-membered monocyclic cyclic group in which 1 to 4 main chain atoms are connected.
  • Examples of the "divalent nitrogen atom optionally having substituent (s)" include not only NH but also a hydrogen atom in the "-NH-" group, optionally (1) an aliphatic hydrocarbon group, ( 2) cyclic group, (3) aliphatic hydrocarbon group substituted by cyclic group, (4) hydroxyl group, (5) 0-aliphatic hydrocarbon group, (6) 0-cyclic group, (7)- O—aliphatic hydrocarbon—cyclic group, (8) -SO—aliphatic hydrocarbon group, (9) -S
  • An aliphatic hydrocarbon group substituted with 1 to 5 substituents selected (b) a cyclic group substituted with 1 to 5 substituents selected from (5) to (55) in the T A group (c) a cyclic group substituted by an aliphatic hydrocarbon group substituted with 1 to 5 substituents selected from (5) to (55) in the T; (d) in the T And those substituted with an aliphatic hydrocarbon group substituted with a cyclic group substituted with 1 to 5 substituents selected from (5) to (55).
  • the “aliphatic hydrocarbon group”, “cyclic group”, and “mono-aliphatic hydrocarbon one” herein have the same meaning as described above.
  • the "divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms” in the “divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms which may have a substituent” For example, Cl to 4 alkylene groups (eg —CH—, — (CH) —, — (CH) —, — (CH) — etc.), C2 to 47 lucerene groups
  • 4-anolylene group eg, one C ⁇ C one, one CH—C ⁇ C, one C ⁇ C—CH—, one (C H) C ⁇ C-one, C ⁇ C-one (CH) -one, CH—C ⁇ C CH—, etc.
  • examples of the “substituent” in the “divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms which may have a substituent” include the substituents exemplified as T above. These optional substituents may be substituted with 1 to 5, preferably 1 to 2, at substitutable positions.
  • the "divalent 3- to 8-membered monocyclic group" in the "divalent 3- to 8-membered monocyclic group which may have a substituent” includes, for example, "3- Examples include divalent groups formed by removing any two hydrogen atoms from an “8-membered monocyclic group”. Examples of the “3- to 8-membered monocyclic group” include “C3- to 8-membered monocyclic carbocycle”, “3- to 8-membered monocyclic heterocycle” and the like. “C3-8 monocyclic carbocycle” includes C3-8 monocyclic unsaturated carbocycles, carbocycles that are partially or fully saturated.
  • Examples of the “C3-8 monocyclic unsaturated carbocyclic ring, a carbocyclic ring partially or entirely saturated” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, And cyclopentene, cyclohexene, cycloheptene, cyclopentene, cyclopentagen, cyclohexagen, cyclohexabutadiene, cyclooctagen, and benzene ring.
  • examples of the “C 3-8 monocyclic aromatic carbocycle” include a benzene ring.
  • the "3- to 8-membered monocyclic heterocycle” includes, for example, "a hetero atom including 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms” 3-8 membered monocyclic heterocycles "and the like.
  • “as a heteroatom, a 3- to 8-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms” includes a hetero atom.
  • heteroatom is a 3 to 8 membered monocyclic unsaturated heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms.
  • ⁇ heterocycles that are completely saturated '' include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, Chepin, oxazole, isoxazole, thiazole, isothiazole, furazane, oxaziazole, oxazine, oxazidine, oxazepine, oxazizepine, thiadiazo Norre, thiazine, thiadiazine, thiazepine, thiazepin
  • Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazonole, isoxazole, thiazol, isothiazole, furazane, oxadiazole, and thiadiazole ring.
  • Examples of the "substituent" in the "divalent 3- to 8-membered monocyclic group which may have a substituent” include the substituents exemplified as the T, and the like. These optional substituents may be substituted with 1 to 8, preferably 1 to 5, at substitutable positions.
  • a spacer having 1 to 10 atoms in the main chain represented by E means an interval in which ⁇ 10 nuclear atoms in the main chain are connected.
  • the “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • Shall count the number of atoms in the main chain as six.
  • Examples of the “spacer having 1 to 10 atoms in the main chain” include —O—, —S—, —CO—, —so—, —SO—, and a substituent.
  • Divalent nitrogen atom having a substituent! /
  • Divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms
  • optionally having a substituent examples thereof include divalent groups having 1 to 10 atoms arbitrarily selected from 3 to 15-membered cyclic groups having 1 to 10 main chain atoms.
  • the “divalent nitrogen atom optionally having substituent (s)” has the same meaning as described above.
  • divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms in the “optionally substituted divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms”, for example, Cl ⁇ 10 Alkylene groups (methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethyle , Heptamethylene, otatamethylene, nonamethylene, decamethylene group and their isomers), C2-10 alkene group (etulene, proberene, butylene, pentylene, hexylene, heptene) -Lene, otatelene, none-lene, decelene group and isomers thereof), C2-10 alkylene group (ethylene, propylene, butylene, pentylene, Hexylene, heptylene, octylene, no-lene, decylene group and isomers thereof).
  • Cl ⁇ 10 Alkylene groups methylene, ethylene, trimethylene, tetramethylene,
  • Examples of the “substituent” in the “divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms which may have a substituent” include the substituents exemplified as the T, These optional substituents may be substituted with 1 to 5, preferably 1 to 2, at substitutable positions! /, Or may be! /.
  • the “divalent 3- to 15-membered cyclic group” in the “divalent 3- to 15-membered cyclic group which may have a substituent” is, for example, “a 3- to 15-membered cyclic group”. And divalent groups formed by removing any two hydrogen atoms.
  • the “3- to 15-membered cyclic group” includes, for example, a C3-15 monocyclic or condensed carbocycle as defined above, a C4-15 bridged carbocycle, or a C7-15 spiro-bonded carbon.
  • Examples of the “substituent” in the “divalent 3- to 15-membered cyclic group which may have a substituent” include the substituents exemplified as the above-mentioned T, and these optional substituents are 1 to 5, preferably 1 to 2 may be substituted at a replaceable position.
  • the "divalent 3- to 8-membered monocyclic group optionally having substituent (s)" represented by E means “having a substituent in B 1 and B 2 ". Thus, it represents the same meaning as “a divalent 3- to 8-membered monocyclic group”.
  • Examples of the “9-: LO member-condensed cyclic group” herein include, for example, “9-: LO member-condensed charcoal”.
  • “9 to 10-membered fused carbocycle” includes 9-: LO-membered unsaturated carbocycles, carbocycles that are partially or fully saturated.
  • Examples of the “9 to 10-membered fused unsaturated carbocyclic ring, a carbocyclic ring partially or completely saturated, include azulene, naphthalene, perhydroazulene, indene, perhydroindene, indane, dihydronaphthalene, And tetrahydronaphthalene, perhydronaphthalene ring, etc.
  • Examples of the “9-: heterocycle condensed with L0 member” include “1-4 nitrogen atoms, 1-2 oxygen atoms as heteroatoms, and Z or a 9 to 10-membered condensed heterocyclic ring containing 1 to 2 sulfur atoms ”and the like.
  • "as a heteroatom, a 9 to 10 membered condensed heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms” includes 9 to 10-membered fused unsaturated heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms, part or all of which are saturated Heterocycles are included.
  • heteroatom is a 9 to 10 membered fused unsaturated heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 to 2 sulfur atoms, part or all of which
  • ⁇ saturated heterocyclic ring '' include, for example, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine , Pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazolone, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, di
  • Examples of the "substituent" in the "divalent 9- to 10-membered condensed heterocyclic ring optionally having substituent” represented by E include the substituents exemplified as the above-mentioned T, etc. These optional substituents may be substituted with 1 to 5, preferably 1 to 2, at substitutable positions.
  • the “divalent 3- to 8-membered monocyclic group optionally having substituent (s)” represented by ring E 1 means “substituent group” in B 1 and B 2. Or the divalent 3- to 8-membered monocyclic group ”.
  • the “divalent 9 to 10-membered condensed cyclic group which may have a substituent” represented by ring E 1 is the “optionally substituted substituent represented by E”. It represents the same meaning as a “valent 9-10 membered condensed heterocyclic ring”.
  • An aliphatic hydrocarbon group means the “aliphatic carbonization”. It has the same meaning as “hydrogen group”.
  • the “spiro-bonded cyclic group” in the “spiro-bonded cyclic group” which may be substituted by a group containing a basic group or may further have a substituent is the above-mentioned “cyclic group” "Means the same meaning as” spiro-bonded cyclic group ". "Substituted by a group containing a basic group
  • the “crosslinked cyclic group” of the “crosslinked cyclic group” which may further have a substituent may have the same meaning as the “crosslinked cyclic group” in the “cyclic group”. Represents. Also
  • substituted herein is not particularly limited.
  • an aliphatic hydrocarbon group which may have a substituent (2) a cyclic group which may have a substituent, (3) a cyclic group which may have a substituent An aliphatic hydrocarbon group substituted with a group, and (4) the substituents exemplified as the T.
  • optionally substituted aliphatic hydrocarbon group may be a cyclic group” and “having a substituent, may be a cyclic group
  • the “aliphatic hydrocarbon group” and the “cyclic group” in the “aliphatic hydrocarbon group substituted with” represent the same meaning as described above, and the “substituent” in (1) to (3) is the substituent exemplified as the above T. These optional substituents may be substituted with 1 to 5 at substitutable positions.
  • a spacer having 1 to 4 atoms in the main chain represented by L means “a spacer having 1 to 4 atoms in the main chain” represented by B 1 and B 2 . It means the same as “Pacer 1”.
  • L A '- (aliphatic hydrocarbon group having carbon atoms of 1 to 3 may have a substituent) - (nitrogen atom which may have a substituent “-” (Nitrogen atom optionally having substituent) in “-” represents the same meaning as the above-mentioned “divalent nitrogen atom optionally having substituent”.
  • aliphatic hydrocarbon group having 1 to 3 carbon atoms in the “optionally substituted aliphatic hydrocarbon group having 1 to 3 carbon atoms”, for example, a Cl to 37 alkylene group (for example, methylene , Ethylene, trimethylene, etc.), C2-37 alkylene groups (eg, etylene, probes, etc.), C2-3 alkylene groups (eg, ethylene, propylene, etc.), etc.
  • substituents in the “C1-C3 aliphatic hydrocarbon group optionally having substituent (s)” include the substituents exemplified as the above-mentioned T, etc. 1 to 3 substituents may be substituted at substitutable positions.
  • L A a divalent carbon number which may have a substituent 1 to The “4 aliphatic hydrocarbon group” has the same meaning as described above.
  • C3-10 monocyclic or bicyclic carbocycle represented by 1 is a C3-l0 monocyclic or bicyclic unsaturated carbocyclic ring, a part of C3-10 Or mono- or bicyclic carbocycles that are all saturated.
  • an oxygen atom and Z or oxidized also good sulfur nuclear also be 3-10 membered monocyclic or bicyclic heterocycle "carbon atoms, the Oxygen atoms and / or sulfur nuclears that may be acidified also become 3-: L0 membered monocyclic or bicyclic unsaturated heterocycles, and carbon atoms, oxygen atoms and Z or even oxidized Also good sulfur nuclear power, partially or fully saturated 3 to: L0 membered monocyclic or bicyclic heterocycles are included.
  • containing at least one nitrogen atom, further oxygen atom or oxidized !, or containing a sulfur atom 3 to: A ⁇ monocyclic or bicyclic heterocyclic ring '' contains at least one nitrogen atom and is further oxygenated or oxidized! /, Or may contain a sulfur atom, or 3 to 10 Containing a monocyclic or bicyclic unsaturated heterocycle with a member and at least one nitrogen atom, and further containing an oxygen atom or oxidized, a sulfur atom, or a part or All are saturated, 3 to: L0 membered monocyclic or bicyclic heterocycles are included.
  • [0136] represented by 2 "substituted by a group containing a basic group, C3-: a monocyclic or bicyclic carbocycle of LO", "substituted by a group containing a basic group, Carbon atom, oxygen atom and / or sulfur atom which may be acidified also become 3-: LO membered monocyclic or bicyclic heterocycle ", or” substituted by a group containing a basic group C3 in the 3 to 10-membered monocyclic or bicyclic heterocyclic ring which may contain at least one nitrogen atom and may further contain an oxygen atom or an optionally oxidized sulfur atom.
  • substituents of the "may be substituted” in 2 is not particularly limited.
  • substituents exemplified as the T may be mentioned, and these optional substituents may be substituted at 1-8, preferably 1-5, at substitutable positions.
  • L A1 is the same as the one in L A — (aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have a substituent) (nitrogen atom which may have a substituent).
  • means represents, 13 and 2 3 may be independently (i) a monocyclic or bicyclic carbon ring C3 ⁇ 10 or (ii) carbon atoms, an oxygen atom and Z or Sani ⁇ Sulfur nuclear power will also be 3-10 members
  • R A represents a group containing a basic group
  • ⁇ [ la and 23 may have 1 to 8 substituents at substitutable positions.
  • the plurality of substituents may be the same or different.
  • L A1 either “optionally substituted aliphatic hydrocarbon group having 1 to 3 carbon atoms” or “optionally substituted nitrogen atom” is ⁇ [ la It is preferable that a “nitrogen atom having a substituent may be bonded to 13 ”, although it may be bonded to. ),
  • L A2 represents the same meaning as the divalent C 1-4 aliphatic hydrocarbon group which may have a substituent in L A , and contains at least one nitrogen atom. Furthermore, an oxygen atom and Z or an acid group, which may contain a sulfur atom, may represent a 3- to 10-membered monocyclic or bicyclic heterocyclic ring, and represents a substitutable position. When there are two or more substituents that may have 1 to 8 substituents, the other substituents may be the same or different. ),
  • ⁇ [contains at least one nitrogen atom which may be substituted with a group containing a basic group, and may further contain an oxygen atom or an optionally oxidized sulfur atom.
  • C3 ⁇ monocyclic or bicyclic carbocycle of LO
  • C3 ⁇ monocyclic or bicyclic carbocycle of LO
  • C3-10 monocyclic or bicyclic carbocyclic ring or "sulphur nuclear power which may be carbon atom, oxygen atom and / or acid is also 3 ⁇ : LO member monocyclic ring Or a “C3-10 monocyclic or bicyclic carbocycle” in a “bicyclic heterocycle” or “a carbon atom, an oxygen atom and Z or a sulfur nuclear power that may be oxidised, also a 3-10 membered monocycle.
  • “Ring or bicyclic heterocycle” has the same meaning as described above. Represented by “containing at least one nitrogen atom which may be substituted by a group containing a basic group, and further containing an oxygen atom or oxidized or containing a sulfur atom.
  • the "group containing a basic group" of R A may be substituted by the above-mentioned "group containing a basic group” or may further have a substituent. It represents the same meaning as the “group containing a basic group” in “a good spiro-bonded cyclic group”.
  • the “substituent” of 13 , ⁇ lb , 2 and “may have 1 to 8 substituents at substitutable positions” is not particularly limited.
  • T Illustrative substituents and the like can be mentioned, and these optional substituents are preferably substituted at 1 to 5 positions at substitutable positions!
  • L A2 may be bonded to a nitrogen atom of 1 NH.
  • substituted include the substituents exemplified as the T.
  • L A may be bonded to the nitrogen atom of —NH—.
  • the nitrogen atom of —NH— may have a substituent.
  • the “substituent” refers to T And the like.
  • substituted with a group containing a basic group which may be substituted with a group represented by J 5 , may be used.
  • the “spiro-bonded cyclic group which may further have a substituent” may be substituted with a group containing a basic group in the foregoing ej, or may further have a substituent.
  • a cyclic group bonded to a spice may be substituted with a group containing a basic group in the foregoing ej, or may further have a substituent.
  • the “carbon atom optionally having substituent (s)” represented by G is —C
  • one to two hydrogen atoms in the “one CH—” group are independently
  • Hydrogen group carboxyl group, COO aliphatic hydrocarbon group, cyano group, nitro group, halogen atom, methyl group substituted by 1 to 3 halogen atoms, methoxy substituted by 1 to 3 halogen atoms A group substituted with an oxo group or the like.
  • the substituents mentioned here have the same meanings as exemplified for T.
  • the "nitrogen atom optionally having substituent (s)" represented by G is a group other than —NH 2, wherein a hydrogen atom in the “—NH—” group is optionally substituted with an aliphatic carbon atom.
  • oxidized sulfur atom means S-, mono-SO-, -SO-.
  • the “monocyclic group” in the “monocyclic group optionally having substituent (s)” represented by ring D is the “substituent” defined in B 1 and B 2 above.
  • examples of the "substituent" in the "monocyclic cyclic group optionally having substituent (s)" represented by ring D include the substituents exemplified as the T, and the like. Arbitrary substituents may be substituted by 1 to 5 at substitutable positions.
  • the “C3-8 monocyclic carbocycle” in the “optionally substituted C3-8 monocyclic carbocycle” represented by ring D includes the aforementioned B 1 and The same meaning as “C3-8 monocyclic carbocycle” in “divalent 3- to 8-membered monocyclic cyclic group which may have a substituent” in B 2 is represented.
  • examples of the “substituent” in the “C3-8 monocyclic carbocyclic ring optionally having substituent (s)” include the substituents exemplified as the above T, and these optional substituents are substituted. You can substitute 1-5 in the possible positions.
  • the “substituent” represented by R 1 is not particularly limited.
  • an aliphatic hydrocarbon group which may have a substituent (2) a cyclic group which may have a substituent, and (3) a substituent which may have Examples thereof include an aliphatic hydrocarbon group substituted with a cyclic group, and (4) the substituents exemplified as the T other than these.
  • “having a substituent may be!
  • an aliphatic hydrocarbon group may be a cyclic group” and “having a substituent,”
  • the “aliphatic hydrocarbon group” and “cyclic group” in the “aliphatic hydrocarbon group substituted with a cyclic group” have the same meaning as described above.
  • Examples of the “substituent” in (1) to (3) herein include the substituents exemplified as the above T, and these optional substituents may be substituted at 1 to 5 substitutable positions. .
  • examples of the “C4-7 monocyclic carbocycle” represented by R 1 include cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene and the like.
  • C1-8 alkyl group represented by R 1 represents the same meaning as the “C1-8 alkyl group” in the aliphatic hydrocarbon group.
  • halogen atom represented by R E
  • - 0- aliphatic hydrocarbon group and "aliphatic hydrocarbon group” has the same meaning as above.
  • an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkylene group, an alkylene group, an alkylidene group and the like include straight-chain and branched-chain ones.
  • isomers (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbon (R, S isomer, a, ⁇ configuration, enantiomers, diastereomers), Optically active substance with optical activity (D, L, d, 1 substance), polar substance by chromatographic separation (high polar substance, low polar substance), equilibrium compound, rotamer, mixture of these in any proportion
  • the racemic mixture is All are included in the present invention.
  • the salts of the compound represented by the general formula (I) include all of low toxicity salts and pharmacologically acceptable salts. Pharmacologically acceptable salts are preferred because they are less toxic and water soluble.
  • a suitable salt of the compound represented by the general formula (I) for example, a salt of an alkali metal (potassium, sodium, lithium, etc.), a salt of an alkaline earth metal (calcium, magnesium, etc.), an ammonium salt (tetra Methylammonium salt, tetraptylammonium salt, etc.), organic amine (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris) (Hydroxymethyl) methylamine, lysine, arginine, N-methyl D-glucamine, etc.), acid adduct salts [inorganic acid salts (hydrochloride,
  • the salt includes quaternary ammonium salt.
  • Quaternary ammonia salt is a general formula (I ) Represents a compound in which the nitrogen atom of the compound is quaternized by the group (R group represents Cl to 8 alkyl group, Cl to 8 alkyl group substituted by a phenyl group).
  • the salt also includes N-oxide.
  • the compound of the present invention can be converted to N-oxide by any method.
  • N-talide represents a compound in which the nitrogen atom of the compound represented by the general formula (I) is oxidized.
  • Suitable solvates of the compound represented by the general formula (I) include solvates such as water and alcohol solvents (for example, methanol, ethanol and the like).
  • the solvate is preferably low toxic and water soluble.
  • the solvates of the compounds of the present invention also include solvates of the alkali (earth) metal salts, ammonium salts, organic amine salts, and acid adduct salts of the compounds of the present invention.
  • the compound of the present invention can be converted to the above salt and the above solvate by a known method.
  • a compound represented by general formula (I), a salt thereof, an N-xide form thereof or a solvate thereof, or a prodrug of these prodrugs is represented by the general formula ( II)
  • M m and M B2 each independently represent a group containing an acidic group, and other symbols have the same meaning as described above.
  • the compound converted into the compound represented by Examples of the prodrug of the compound represented by the general formula (I) include a compound representing a group containing an acidic group in which M B1 and M B2 are protected by a protecting group in the general formula (I).
  • the compound represented by the general formula (I) has an amino group
  • the compound in which the amino group is acylated, alkylated or phosphorylated for example, a compound represented by the general formula (I)
  • the amino group is Eicosa Nylation, arylation, pentylaminocarbolation, (5-methyl-2-oxo-1,3-dioxolene-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethyl , Bivalyloxymethylation, acetoxymethylation, tert-butylated compounds, etc.); when the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated, al
  • prodrug of the compound represented by the general formula (I) may be a hydrate or non-hydrate! /. These compounds can be produced by these known methods.
  • the prodrug of the compound represented by the general formula (I) may be a hydrate or non-hydrate!
  • prodrugs of the compounds represented by the general formula (I) are physiological conditions such as those described in Yodogawa Shoten 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. Or a compound represented by the general formula (I).
  • the compound represented by the general formula (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 1251, etc.).
  • the compound represented by the general formula (I) of the present invention a salt thereof, an N-xide form thereof or a solvent thereof, or a prodrug thereof (hereinafter sometimes abbreviated as a compound of the present invention) It is a compound with excellent solubility and oral absorption, long-lasting pharmacological activity, and low toxicity due to weak inhibition of drug metabolizing enzymes. These properties are the most important properties required for development as pharmaceuticals. It is shown in the “Agnosis and Therapy” (17th edition), The Merck Manual of Diagnosis and Therapy (17th Ed.), Merck & Co. Since the compound of the present invention satisfies these conditions, it has the potential to be a very excellent pharmaceutical product.
  • the “nitrogen-containing heterocycle” in the “nitrogen-containing heterocycle optionally having substituents” represented by A 1 and A 2 is preferably imidazole, benzimidazole, pyridine, etc. Is mentioned. However, A 1 and A 2 may be the same or different.
  • Nitrogen-containing heterocycle” represented by A 1 and A 2 is preferably, for example, absent, an aliphatic hydrocarbon group, the T An aliphatic hydrocarbon group substituted with 1 to 5 substituents selected from (5) to (26), (29) to (32) and (37) to (55) More preferably, for example, absent, substituted with an alkyl group of Cl to 4 (eg, methyl, ethyl, propyl, isopropyl, butyl, sec butyl, tert butyl group, etc.), an oxo group and a mono- or di-substituted amino group An aliphatic hydrocarbon group, and more preferably, non-existent, methyl, dimethylacetamide group and the like can be mentioned.
  • an alkyl group of Cl to 4 eg, methyl, ethyl, propyl, isopropyl, butyl, sec butyl, tert butyl group, etc.
  • a 1 and A 2 are preferably, for example, 1H-imidazole-2-yl, 1-methyl-1H imidazole-2-yl, 2- (1H-imidazole-1yl) -N, N dimethylacetamide, 1 isobutyl-1H —Imidazole-2-yl, 3-methyl-2-pyridyl and the like can be mentioned, and more preferred examples include 1H-imidazole-2-yl, 1-methyl-1H-imidazole-2-yl and the like.
  • the ring A 1B and the ring A 2B represented by "having a substituent! / ⁇ may! / ⁇ imidazole, having a substituent may be a benzo
  • Preferred as the “substituent” of the “pyridine ring” having imidazole or a substituent is preferably absent, for example, an aliphatic hydrocarbon group, an oxo group and an aliphatic group substituted with a mono- or di-substituted amino group A hydrocarbon group etc. are mentioned, More preferably, a non-existing, Cl-4 alkyl group, N, N dimethylacetamide etc. are mentioned, for example.
  • B 1 and B 2 are preferably a spacer having 1 atom in the main chain, and more preferably CO, 1 SO-, or a substituent. Good methylene group (one CH-)
  • B 1 and B 2 may be the same or different.
  • G is preferably a bond, a carbon atom which may have a substituent, a sulfur atom which may be oxidized, or the like (which may have a substituent). Carbon atom) ⁇ (nitrogen atom which may have a substituent).
  • the “substituent” herein is preferably, for example, absent, a methyl group or an oxo group, and more preferably absent, an oxo group. More preferably, G is a bond, CO, 1 SO, 1 CH —, 1
  • E is preferably, for example, a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms which may have a substituent, or a divalent which may have a substituent.
  • An optional divalent 3- to 8-membered monocyclic group has the same meaning as defined in B 1 and B 2 above.
  • the “3- to 8-membered monocyclic group” is preferably a C5-C7 monocyclic carbocyclic ring (the C3-C8 monocyclic carbocyclic force having 5 to 7 carbon atoms is selected).
  • 5 to 7-membered monocyclic heterocycle (the above-mentioned 3 to 8 membered monocyclic heterocyclic ring having 5 to 7 members is selected), and more preferably, for example, cyclo Pentane, cyclohexane, cycloheptane, cyclohexene, cyclohexane, benzene, pyridine, pyrazine, pyrimidin, pyridazine, piperidine, piperazine ring, etc., particularly preferably benzene, cyclohexane ring It is.
  • the “9 to 10-membered condensed cyclic group in the“ divalent 9 to 10-membered condensed cyclic group which may have a substituent ”” is preferably a 9 to 10-membered condensed heterocyclic ring, More preferably, a tetrahydroisoquinoline ring is mentioned, for example.
  • a substituent it may be a divalent 3- to 8-membered monocyclic group or "With a substituent, V may be a divalent 9- to 10-membered group”
  • the “substituent” of the “fused cyclic group” is preferably, for example, absent, a halogen atom or an aliphatic hydrocarbon group, and more preferably absent. is there.
  • halogen atom and “aliphatic hydrocarbon group” have the same meaning as described above.
  • the ring E 1 is preferably a divalent 3- to 8-membered monocyclic group which may have a substituent, for example.
  • Preferred examples of the “monocyclic ring group” include cyclopentane, cyclohexane, benzene, pyrrolidine, and piperidine ring.
  • the “substituent” here is preferably non-existent, aliphatic hydrocarbon group, halogen atom and the like.
  • L is preferably a spacer having 1 to 2 atoms in the main chain among the spacers having 1 to 4 atoms in the main chain.
  • the “spacer having 1 to 2 atoms in the main chain” is preferably —0—, —S—, —CO—, —SO—, and has a substituent.
  • a divalent nitrogen atom having a substituent! /, Or may be any one selected from a divalent aliphatic hydrocarbon group having 1 carbon atom.
  • one CO Preferably, for example, one CO, one CH—, one CONH—, —CH—NH, one O—
  • the “substituent” of the “divalent nitrogen atom with a substituent” is preferably absent or an aliphatic hydrocarbon group substituted with an aliphatic hydrocarbon group or a carboxyl group.
  • J is preferably "substituted with a group containing a basic group, and further having a substituent! / ?” a cyclic group", "containing a basic group A spiro-bonded cyclic group which may be substituted by a group which may further have a substituent.
  • the “cyclic group” here is preferably a spiro-bonded cyclic group or the like. "Contains basic groups The “spiro-bonded cyclic group” in the “spiro-bonded cyclic group” and the “spiro-bonded cyclic group” in the “cyclic group” Preferably, 2, 7 diazaspiro [3.5] nonane, 2, 8 diazaspiro [4.
  • the “spiro-bound cyclic group” is preferably 2, 7 diazaspiro [3.5] nonane, 2, 8 diazaspiro [4. 5] decane, 2, 7 diazaspiro [4. 5] decane, 2, 9 diaza spiro.
  • spiro-bound cyclic group is 2, 7 diazaspiro [4. 5] decane, 2, 8 diazaspiro [4. 5] decane, 2, 8 diazaspiro [5. 5] undecane, 2, 9 Gizaspiro [5.5] undecane, 2, 7 Zazaspiro [3.5] nonane, 1-oxa 4, 9 diazaspiro [5.5] undecane ring.
  • this specification is preferably a "location substituent" of "optionally substituted with a substituent" of J 5, fat substituted aliphatic hydrocarbon group, a cyclic group, the cyclic group An aliphatic hydrocarbon group and the like, more preferably an aliphatic hydrocarbon group having 1 to 8 carbon atoms, and a C3-10 monocyclic or bicyclic carbocycle.
  • 2 and J 5 contain "basic group” which is "substituted by a group containing a basic group” or “may be substituted by a basic group” Preferred as ⁇ substituent '' Examples thereof include a mono- or di-substituted amino group and a nitrogen-containing bicyclic group which may have a substituent.
  • the “mono- or di-substituted amino group” herein is preferably a di-substituted amino group or the like, and more preferably, for example, a dimethylamino-containing dimethylamino-containing dipropylamino, dibutylamino, N-cyclohexyl-N-propylamino or the like.
  • dipropylamino-containing N-cyclohexyl N-propylamino is particularly preferred.
  • the “nitrogen-containing heterocyclic group optionally having substituent (s)” here is preferably a piperidine, azetidin, morpholine, pyrrolidine, piperazine ring or the like, more preferably a piperidine ring.
  • substituent of “mono-substituted amino group” of “mono- or di-substituted amino group” are preferable.
  • L A may be bonded to the nitrogen atom of NH, and the nitrogen atom of NH may have a substituent.
  • the “substituent” here is exemplified as T. More preferably, L B -J 6 (wherein all symbols have the same meanings as described above).
  • J 6 is preferably, for example,
  • L B is preferably CO—, —CH—, —CH—CH— or the like.
  • R 1 is preferably an aliphatic hydrocarbon group which may have a substituent, an aliphatic hydrocarbon group which may have a substituent, an aliphatic hydrocarbon group which is substituted with a cyclic group, or a substituent. Have it! And a cyclic group.
  • R 1 represents “having a substituent! /, May! /, An aliphatic hydrocarbon group” and “having a substituent, which may be an aliphatic group substituted with a cyclic group”
  • the “aliphatic hydrocarbon group” of the “hydrocarbon group” preferably includes a Cl-8 alkyl group, and more preferably, for example, sec-butyl, tert butyl, pentyl and the like.
  • the “cyclic group” of the “cyclic group” represented by R 1 is preferably a C3-15 monocyclic or condensed unsaturated carbocyclic ring, part or all of which Such as saturated carbocycles. More preferred are C3-8 monocyclic saturated carbocycles, and particularly preferred are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane rings and the like.
  • the “substituent” of the “optionally substituted aliphatic hydrocarbon group” preferably cyclopentane, Cyclohexane, thiophene, and benzene rings.
  • the “cyclic group” of the “aliphatic hydrocarbon group substituted with an optionally substituted cyclic group” is preferably a thiophene ring.
  • M A1 and M A2 are preferably one (Y 1 ) — Z A.
  • group containing an acidic group optionally protected by a protecting group and “group containing an acidic group protected by a protecting group” represented by M A1 and M A2
  • the “acidic group” is preferably a carboxyl group, a sulfo group (SO H), a sulfino group (S
  • the “protecting group” of the “group containing an acidic group optionally protected by a protecting group” represented by M A1 and M A2 preferably has a substituent! /
  • a hydrocarbon group may be mentioned, more preferably, for example, a Cl-8 alkyl group, a hydrocarbon group substituted with an aminocarbonyl group substituted with a Cl-8 hydrocarbon, or other than a carbon atom.
  • pi and p2 are preferably pi force, force p2 force, or pi is 1 and p2 is 0.
  • Y 1 is preferably a methylene group optionally having 1 to 2 substituents.
  • R 1Y and R 2Y are preferably a hydrogen atom or an aliphatic hydrocarbon group.
  • Y 2 and Y 3 are preferably a methylene group optionally having 1 to 2 substituents.
  • q is preferably an integer of 1 to 4, more preferably an integer of 1 to 2.
  • Z A is preferably a carboxyl group which may be protected by a protecting group.
  • the “hydrocarbon group” in (2) here has the same meaning as the “hydrocarbon group” in the “hydrocarbon group which may have a substituent.”
  • the “5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, and Z or nitrogen atom other than carbon atom” in (3) here is preferably, for example, 2 or 3 chails, 2 or 3 furyl, 3—, 4 or 5 pyrazolyl, 4—tetrahydroviranyl, 2—, 4 or 5 thiazolyl, 3—, 4 or 5 isothiazolyl, 2—, 4 or 5—oxazolyl, 3 —, 4 or 5—isoxazolyl, 2—, 4 or 5—imidazolyl, 1, 2, 3 or 1, 2,4 triazolyl, 1H or 2H—tetrazolyl, 2—, 3 or 4 pyridyl, 2—, 4 Or 5-pyrimidinole, 3 or 4 pyridanidy
  • the "monocyclic group" in the “monocyclic group optionally having substituent (s)" represented by ring D is preferably, for example, a C3-8 monocyclic carbocycle. Is mentioned.
  • C3-8 monocyclic group" of the "optionally substituted C3-8 monocyclic group” represented by ring D is preferably, for example, C3-8 saturated monocyclic groups are preferred, and C3-8 saturated monocyclic groups are preferably cyclopentane, cyclohexane, cycloheptane and the like.
  • R E is preferably an aliphatic hydrocarbon group.
  • t is preferably 0 or 1.
  • preferred compounds include those represented by the general formula (1-1)
  • ring D 1 represents a C3-8 monocyclic carbocyclic ring, and other symbols have the same meaning as described above.
  • preferred compounds include, for example, (2- ⁇
  • Preferred compounds of the present invention include the compounds described in the examples, salts thereof, N-oxides thereof or solvates thereof, prodrugs thereof and the like.
  • Further preferred compounds of the present invention include (2- ⁇ [ ⁇ 4 [(8 cyclohexyl 2,8-diazaspiro [4.5] deca-2-yl) methyl] benzyl ⁇ (1H-imidazole-2-ylmethyl) Amino] methyl ⁇ 1H-imidazole-1yl) acetic acid, ethyl (2— ⁇ [ ⁇ 4 -— [(8 cyclohexyl 2,8 diazaspiro [4.5] dec-2-yl) methyl] benzyl ⁇ (1H-imidazole 2-ylmethyl) amino] methyl ⁇ -1H-imidazole-1-yl) acetate, ethinole 3— (2— ⁇ [ ⁇ 4— [(8 cyclohexyl 2, 8 diazaspiro [4 .5] deca 2— L) Methyl] benzyl ⁇ (1H-imidazole-2-ylmethyl) amino] methyl ⁇ 1H-imidazole
  • the compounds of the present invention represented by the general formula (I) can be prepared by known methods, for example, the methods shown below, the methods described in the examples, or the comprehensive 'organic' transformations (omprehensive organic transformations: The method described in A Guide to Functional Group Preparations, 2nd edition (Richard Clarock, John Wiley & Sons Inc, 1999) can be manufactured by appropriately modifying and combining the methods.
  • the raw material mixture may be used as a salt.
  • those described as the salt of the compound represented by the general formula (I) are used.
  • W represents a hydroxyl group or a chlorine atom, and other symbols have the same meaning as described above.
  • the compound represented by can be produced by subjecting it to an amidation reaction, and further subjecting to a deprotection reaction of a protecting group and a cleavage reaction from Z or rosin if desired.
  • a method using an acid or a halide includes, for example, a carboxylic acid in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.) or without a solvent, and an acid halide agent (oxalyl chloride, Reaction with thionyl chloride, etc. at ⁇ 20 ° C to reflux temperature, and the resulting acid halide is converted into a base (pyridine, triethylamine, N, N-dimethylaline, 4-diphenyl).
  • an organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.
  • an acid halide agent oxalyl chloride, Reaction with thionyl chloride, etc. at ⁇ 20 ° C to reflux temperature
  • an organic solvent chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.
  • ammine at 0 to 40 ° C in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (sodium bicarbonate or sodium hydroxide solution, etc.). It can also be done.
  • the method using a mixed acid anhydride is, for example, by using a carboxylic acid in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.) or without a solvent, and with a base (pyridine, triethylamine).
  • an organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.
  • a base pyridine, triethylamine
  • a method using a condensing agent includes, for example, a method in which a carboxylic acid and an amine are mixed with a base (pyridine , Triethylamine, diisopropylethylamine, N, N dimethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) in the presence or absence of a condensing agent (1,3 dicyclohexyl carpositimide) (DCC), 1-ethyl 3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1, 1'-carbodiimidazole (CDI), O- (7-azabenzotriazole- 1—Nyl) N, N, ⁇ ', ⁇ '— Tetramethyl-mu-hexafluorophosphate (HATU), 2--Chloro-mono- 1-methyl pyridi-mu-iodine, 1-propylphosphonic acid cyclic anhydride
  • DCC
  • the reactions (1), (2) and (3) are all preferably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • an inert gas argon, nitrogen, etc.
  • the deprotection reaction of the protecting group can be carried out by a known method, for example, protective 'groups' in It can be performed using the method described in Protective Groups in Organic Synthesis (TWGreene, John Wiley & Sons Inc, 1999). Further, the protecting group is not particularly limited as long as it is one described in the above-mentioned literature or other group that can be easily and selectively eliminated.
  • the compound of the present invention can be cleaved from the resin by the following method.
  • This cleavage reaction from rosin is known, for example, using an acid (acetic acid, trifluoroacetic acid, hydrochloric acid, etc.) in an organic solvent (dichloromethane, 1,2-dichloroethane, toluene, etc.), 0 to: The reaction is performed at L00 ° C.
  • this reaction may be followed by an operation for conversion to the target salt by a known method.
  • the sulfonamido reaction is known and can be carried out by the following method.
  • sulfonic acid can be used in an organic solvent (such as chloroform, dichloromethane, dichloroethane, jetyl ether, tetrahydrofuran, methyl tert butyl ether) or without any solvent.
  • organic solvent such as chloroform, dichloromethane, dichloroethane, jetyl ether, tetrahydrofuran, methyl tert butyl ether
  • sulfonyl can be synthesized by reacting thiol with an aqueous acid solution (eg, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc.) and chlorine gas at 0 ° C. to reflux temperature.
  • aqueous acid solution eg, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc.
  • chlorine gas at 0 ° C. to reflux temperature.
  • the sulphonyl halide synthesized above is prepared in the presence of a base (diisopropylethylamine, pyridine, triethylamine, N, N dimethylamine, 4-dimethylaminopyridine, etc.) in an organic solvent (chloroform, dichloromethane, dichloroethane).
  • the deprotection reaction of the protecting group or the cleavage reaction from the resin can be carried out by the same method as described above.
  • It can be produced by subjecting the compound represented by the above to a urea reaction, and further subjecting to a deprotection reaction of a protecting group and a cleavage reaction from Z or rosin if desired.
  • This urealation reaction is publicly known.
  • the compound represented by the general formula (2) is converted into an organic solvent.
  • This reaction is desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • inert gas argon, nitrogen, etc.
  • the deprotection reaction of the protecting group or the cleavage reaction from the resin can be carried out by the same method as described above.
  • this reaction may be followed by an operation for conversion to the target salt by a known method.
  • R represents a hydrogen atom or a substituent or a hydrogen atom in" a divalent nitrogen atom having a substituent, as defined in L ", and the other symbols are the same as above. Expresses meaning
  • the compound represented by formula (8) may be subjected to an amidy reaction and, if desired, subjected to a deprotection reaction of a protecting group and a cleavage reaction from Z or a resin.
  • the compound represented by can be produced by subjecting it to an amidation reaction, and further subjecting to a deprotection reaction of a protecting group and a cleavage reaction from Z or rosin if desired.
  • Amidation reaction, deprotection reaction of protecting group or cleaving reaction from rosin are the same methods Can be done by.
  • the compound represented by formula (8) is subjected to a sulfonamidation reaction, and if desired, further subjected to a deprotection reaction of a protecting group and a cleavage reaction from Z or rosin, or a compound represented by formula (8) )
  • the sulfonamidation reaction, the deprotection reaction of the protecting group, or the cleavage reaction from the resin can be carried out by the same method as described above.
  • the amidation reaction, the deprotection reaction of the protecting group, or the cleavage reaction from the resin can be carried out by the same method as described above.
  • the sulfonamidation reaction, the deprotection reaction of the protecting group, or the cleavage reaction from the resin can be carried out by the same method as described above.
  • G represents a carbon atom which may have one substituent, and is a divalent group adjacent to the nitrogen atom in B 1 and B 2 Is — CH—
  • B 2K represents a bonder or a spacer having 1 to 3 atoms in the main chain
  • R M1 is a hydrogen atom, or “an optionally substituted carbon atom” defined in G
  • the other symbols have the same meaning as described above.
  • This reductive amination reaction is known, for example, in an organic solvent (dichloroethane, dichloromethane, dimethylformamide, acetic acid, and a mixture thereof) in a reducing agent (sodium tricetoxyborohydride, sodium cyanoborohydride, In the presence of sodium borohydride and the like) at a temperature of 0 to 40 ° C.
  • a reducing agent sodium tricetoxyborohydride, sodium cyanoborohydride, In the presence of sodium borohydride and the like
  • the reductive amination reaction, the deprotection reaction of the protecting group, or the cleavage reaction from the resin can be carried out by the same method as described above.
  • the compound represented by the general formula (18) or the general formula (19) is subjected to a reductive amination reaction, and further optionally subjected to a deprotection reaction of a protecting group and a cleavage reaction from Z or a resin. Can be manufactured.
  • the reductive amination reaction, the deprotection reaction of the protecting group or the cleavage reaction from the resin can be carried out by the same method as described above.
  • a divalent group that represents an A ⁇ A 2 force S imidazol-2-yl group and is adjacent to the nitrogen atom in B 1 and B 2 Is —CH— and pi is 1.
  • the reductive amination reaction, the deprotection reaction of the protecting group, or the cleavage method from the resin can be carried out by the same reaction as described above.
  • M A1 is an acidic group protected by a protective group, the acidic group is — (CR 1Y R Y2 ) — COOH, and pi is I compound representing 1
  • This alkylation reaction is known, for example, in an organic solvent (eg, dimethylformamide, dimethylsulfoxide, etc.), alkali (potassium carbonate, sodium carbonate, triethylamine, etc.) and sodium iodide or potassium iodide. About 0-15 in the presence or absence of an organic solvent (eg, dimethylformamide, dimethylsulfoxide, etc.), alkali (potassium carbonate, sodium carbonate, triethylamine, etc.) and sodium iodide or potassium iodide. About 0-15 in the presence or absence
  • This reaction is preferably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • inert gas argon, nitrogen, etc.
  • the compound represented by (23) is a force known per se, or a known method such as Comprehensive Organic Transformations: A Guide to Functional uroup Preparations ⁇ It can be easily produced by using a combination of the methods described by arcock, John Wiley & Sons Inc, 1999).
  • reaction involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.
  • a solid-phase-supported reagent supported on a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • the reaction product is purified by an ordinary purification means such as normal pressure. Or purify by low pressure distillation, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin, column chromatography or washing, recrystallization, etc. You can. Purification may be performed for each reaction or after completion of several reactions.
  • the reaction product is obtained by a conventional purification method such as a solvent (N, N-dimethylformamide, dichloromethane, methanol, tetrahydrofuran, toluene, acetic acid Z). It can be purified by washing multiple times with toluene.
  • a solvent N, N-dimethylformamide, dichloromethane, methanol, tetrahydrofuran, toluene, acetic acid Z.
  • the toxicity of the compound of the present invention is very low, and it can be judged that the compound is sufficiently safe for use as a medicine.
  • the compounds of the present invention have CXCR4 antagonistic activity, and C XCR4 mediated diseases such as inflammation'immune diseases, allergic diseases, infectious diseases, particularly HIV infection and associated diseases It is effective for prevention and Z or treatment of mental 'neurological disease, brain disease, cardiovascular disease, metabolic disease, cancer disease. It is also useful as a regenerative medicine agent for the purpose of in vitro or in vivo amplification of stem cells for gene therapy, peripheral blood stem cell mobilization, tissue repair, and the like. Among regenerative medicine, it is useful as a medical agent for transplantation used for various organ transplantation including bone marrow transplantation, peripheral blood stem cell transplantation, and tissue repair. Furthermore, it is also useful as an angiogenesis inhibitor effective for the prevention and Z or treatment of diseases caused by angiogenesis such as retinopathy (diabetic retinopathy, etc.), macular degeneration, and cancer growth.
  • CXCR4 antagonistic activity and C XCR4 mediated diseases such as inflammation'immune diseases, allergic diseases, infectious diseases
  • Inflammation 'immunological diseases include, for example, rheumatoid arthritis, arthritis, retinopathy, gout, organ rejection, graft-versus-host disease (GVHD), nephritis, psoriasis, rhinitis, conjunctivitis, multiple sclerosis, Examples include ulcerative colitis, Crohn's disease, shock associated with bacterial infection, pulmonary fibrosis, systemic response syndrome (S IRS), acute lung injury, and diabetes.
  • GVHD graft-versus-host disease
  • S IRS systemic response syndrome
  • allergic diseases include asthma, atopic dermatitis, rhinitis, conjunctivitis and the like.
  • Infectious diseases include streptococci (Group A ⁇ -streptococci, pneumococci, etc.), Staphylococcus aureus (MSS A, MRSA), Staphylococcus epidermidis, enterococci, Listeria, meningococcus, bacillus, pathogenic colon Bacteria (0157: ⁇ 7, etc.), Klebsiella (Klebsiella pneumoniae), Proteus, Pertussis, Pseudomonas aeruginosa, Serratia, Citropactor, Acinetopacter, Enteropacter, Mycoplasma, Chlamydia, Clostridium, etc., cholera, diphtheria, dysentery, scarlet fever, Anthrax, tracosis, syphilis, tetanus,
  • HIV infection and associated diseases include, for example, acquired immune deficiency syndrome ( ⁇ DS), candidiasis, cali-pneumonia, cytomegalovirus retinitis, force positive sarcoma, malignant lymphoma, AIDS encephalopathy, bacteria Septicemia and the like.
  • ⁇ DS acquired immune deficiency syndrome
  • candidiasis candidiasis
  • cali-pneumonia cytomegalovirus retinitis
  • force positive sarcoma malignant lymphoma
  • AIDS encephalopathy bacteria Septicemia and the like.
  • Examples of the psychiatric / neurological disease and brain disease include dementia including Alzheimer's disease, Parkinson's disease, stroke, cerebral infarction, cerebral hemorrhage, epilepsy, schizophrenia, peripheral neuropathy and the like.
  • Cardiovascular diseases include, for example, arteriosclerosis, ischemia-reperfusion injury, hypertension, myocardial infarction
  • Angina pectoris heart failure and the like.
  • Examples of metabolic diseases include diabetes, osteoporosis, enlarged prostate and frequent urination.
  • Macular degeneration is a disease in which progressive damage occurs in the macular, which is an important part of the retina at the center of the retina. Among them, an age-related macular degeneration is called age-related macular degeneration. Macular degeneration includes an atrophic type (dryness) in which macular tissue atrophy with age, and an exudative type (wetness) in which new blood vessels are generated from the choroid in the macular region.
  • cancer diseases include malignant tumors such as breast cancer, brain tumor, and malignant lymphoma, cancer metastasis, and release.
  • Radiation therapy z include myelosuppression or thrombocytopenia after chemotherapy.
  • the compounds of the present invention are also effective for the prevention and Z or treatment of cancer diseases or infectious diseases, and preferably effective for cancer diseases.
  • the CYP2C9 inhibitory activity of the compounds of the present invention can be evaluated by adding improvements in measurement accuracy and Z or measurement sensitivity.
  • the compound of the present invention is appropriately improved by appropriately improving the method described in "DRUG METABOLISM AND DISPOSITION, Vol. 28, No. 12, 1440-1448, 2000". Can be evaluated.
  • test compound can be administered once intravenously or once orally, and the toxicity can be examined in comparison with the vehicle administration group. It can be evaluated by performing basic toxicity assessments such as general state observation and spontaneous motor observation.
  • HEK293 cells were used to measure the hERG I current induced by the repolarization pulse following the depolarization pulse. Measure the maximum tail current using the patch clamp method, and calculate the rate of change (suppression rate) 10 minutes after application of the test substance to the maximum tail current before application of the test substance.
  • the influence on the Kr current can be evaluated based on this suppression rate.
  • the measurement methods (1) to (2) described above are not limited to the above-described methods, and it is possible to utilize conventional methods based on basic methods. .
  • the above-described measurement method may add an improvement in measurement accuracy and an improvement in Z or measurement sensitivity in order to evaluate the compound of the present invention.
  • the compound of the present invention may be combined and administered as a concomitant drug.
  • the combined use of the compound of the present invention and other drugs may be administered in the form of a combination preparation in which both components are combined in one preparation, or may be administered in separate preparations.
  • simultaneous administration and administration by time lag are included.
  • administration by time difference may be such that the compound of the present invention is administered first and the other drug is administered later, or the other compound is administered first and the compound of the present invention is administered later.
  • Each administration method is the same or different!
  • the preventive and Z or therapeutic effects are not particularly limited by the above combination drug. Any disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention may be used.
  • the mass ratio of the compound of the present invention and the other drug is not particularly limited.
  • HIV infection and acquired immune deficiency syndrome prevention and Z or treatment agents used in combination with the compounds of the present invention include reverse transcriptase inhibitors, protease inhibitors, chemokines (eg, CCR2 , CCR3, CCR4, CCR5, CXCR4, etc.) antagonists, CD4 antagonists, antibodies to surface antigens of HIV (eg, HIV-1, HIV-2, etc.), HIV (eg, HIV-1, HIV-2, etc.) Vaccines, HIV-related short interfering RNA, and the like.
  • chemokines eg, CCR2 , CCR3, CCR4, CCR5, CXCR4, etc.
  • CD4 antagonists eg, antibodies to surface antigens of HIV (eg, HIV-1, HIV-2, etc.), HIV (eg, HIV-1, HIV-2, etc.) Vaccines, HIV-related short interfering RNA, and the like.
  • reverse transcriptase inhibitors examples include: (1) Nucleotide-based reverse transcriptase inhibitors zidovudine (trade name: Retrovir), didanosine (trade name: Vuyedettas), zalcitabine (trade name: hibid), stavudine ( (Product name: Zelit), Lamivudine (Product name: Epepivir), Abba Power Building (Product name: Ziagen), Dianosin (Product name: Vidic), Adefovir, Dipivoxil, Entrycitabine (Product name: Neviracil), Tenofovir ( (Product name: Billiard), Combi, Trigivir, Torbata, Ibigem, etc.
  • Nevirabin (Product name: Viramune), Delavirdine (Product name: Rescrypter), EFavirenz (Product name) : Sustaino, Stocklin), Kabrau Ylin (AG1549), etc.
  • Protease inhibitors include, for example, indinavir (trade name: tarixiban), ritonavir (trade name: novia), nelfinavir (trade name: viracebut), saquinavir (trade name: inbilase, fort base), amplinavir (Product name: Eginerase), Mouth pinavir (Product name: Kaletra), Atazanavir ((Product name: Leatas), Fosamprenavir (Product name: Rexiva), Tibranavir, etc.
  • Chemokine antagonists include, for example, endogenous ligands for chemokine receptors, or derivatives and non-peptide low-molecular compounds, or chemokine receptors. Antibody and the like.
  • Endogenous ligands of chemokine receptors include, for example, MIP-1a, MIP-1 ⁇ , RANTES, SDF-1a, SDF-1 ⁇ , MCP-1, MCP-2, MCP-4, Examples include Eotaxin and MDC.
  • Examples of the endogenous ligand derivative include AOP-RANTES, Met-SDF-1a, Met-SDF-lj8, and the like.
  • chemokine receptor antibodies examples include Pro-140 and the like.
  • CCR2 antagonists include WO99 / 07351, WO99 / 40913, WO00 / 46195, WO00 / 46196, WO00. / 46197 pamphlet, WO 00/46198 pamphlet, WO 00/46199 pamphlet, WO 00/69432 pamphlet, International publication 00/69815 pamphlet or Bioorg. Med. Chem. Lett ., 10, 1803 (2000).
  • CCR3 antagonists include DE19837386 pamphlet, WO99 / 55324 pamphlet, WO99 / 55330 pamphlet, WO00 / 04003 pamphlet, WO00 / 27800 pamphlet.
  • Examples of the CCR4 antagonist include compounds described in WO 02/030357 pamphlet and WO 02/030358 pamphlet.
  • CD4 antagonists include curdlan sulfate, TNX-355, BT-061, CD4 antagonist 802-2, 4162W94, PP 0102, anti-CD4 antibody, AD-519, TRX-1, CD4 IgG Etc.
  • CXCR4 antagonists include AMD-3100, AMD-070, T22, KRH-1 120, KRH-1636, KRH-2733, CS-3955, International Publication No. 00/66112 Pamphlet, International Publication No. 2004024697, International Publication No. 2004052862 International Publication 2006022454, International Publication 2006023400, International Publication 2006020415, International Publication 2006020891, International Publication 2006036816, United States Patent Publication 2006069122, International Publication 2006034001 International Publication No. 2006028896, International Publication No. 2006048862, International Publication No. 2006074426, United States Patent Publication No. 2006160860, International Publication No.
  • Examples of the fusion inhibitor include T-20 (pentafoside, Enfovirtide, Fuseon (trade name)), T-1249, and the like.
  • HIV integrase inhibitors examples include Equisetin, Temacrazine, MK0518 (Raltegravir), PL-2500, V-165, NSC-618929, L-870810, L-708906 analog, S- 1360, 1838 and so on.
  • HIV-related short interfering RNA is a short interfering RNA that targets the gene of an HIV-related factor.
  • Factors related to HIV include reverse transcriptase, protease, chemokine (eg, CCR2, CCR3, CCR4, CCR5, CXCR4, etc.), CD4, HIV (HIV-1, HIV-2, etc.), and the like.
  • Examples of HIV-related short interfering RNA include GPs-0193, HGTV-43, GEM-132, GEM-92, GEM-93, HYB-0184, GEM-91, UL36ANTI, ISIS-2922, ISIS-14803, GPI-2A, R-95288, VRX-496, etc.
  • Typical clinical dosages of typical reverse transcriptase inhibitors and protease inhibitors are: For example, as shown below, the present invention is not limited to these.
  • Zidovudine lOOmg capsenore, 200mg once, 3 times daily; 300mg tablet, 300mg once, twice daily;
  • Didanosine 25-200 mg tablet, 125-200 mg once, twice daily;
  • Zalcitabine 0.375mg to 0.75mg tablet, 0.75mg once, 3 times daily;
  • Stavudine 15-40 mg capsule, 30-40 mg once, twice daily;
  • Lamivudine 150mg tablet, 150mg once, twice daily;
  • Nevirapine 200 mg tablet, 200 mg once, 14 days once daily, then twice daily;
  • Delavirdine lOOmg tablet, 400mg once, 3 times daily;
  • Favirenz 50-200mg capsule, once 600mg, once a day;
  • Indinavir 200-400mg capsule, 800mg once, 3 times daily;
  • Ritonavir lOOmg capsule, 600mg once, twice daily;
  • Nelfinavir 250mg tablet, 750mg once, 3 times daily;
  • Saquinavir 200mg capsule, 1 l, 200mg, 3 times a day;
  • Amprenavir 50-150 mg tablet, 1 l, 200 mg, 2 times a day.
  • drugs for the prevention and Z or therapeutic effect supplementation and Z or enhancement of asthma of the compounds of the present invention include, for example, antihistamines, antiallergic drugs Histamine antagonists, thromboxane synthase inhibitors, thromboxane antagonists, Th2 site force-in inhibitors), steroids, bronchodilators (xanthine derivatives, sympathomimetic drugs, parasympathomimetic drugs), vaccine therapies , Gold preparation, Chinese medicine, basic non-steroidal anti-inflammatory drug, 5-lipoxygenase inhibitor, 5-lipoxygenase activity, protein antagonist, leukotriene synthesis inhibitor, prostaglandins, cannapinoid 2 receptor agonist, antitussive, An expectorant and the like.
  • Antihistamines include, for example, diphenhydramine, diphenylviralin hydrochloride, diphenyl-bibilylline teolate, clemastine fumarate, dimenhydrinate, dl-chlorferramine maleate, d-chlorfelamine maleate, Triprolidine hydrochloride, promethazine hydrochloride, alimemazine tartrate, isothipentyl hydrochloride, homochlorcyclidine hydrochloride, hydroxy Gin, Cyproheptadine hydrochloride, Levocabastine hydrochloride, Astemizole, Bepotastine, Desloratadine, TAK—427, ZCR—2060, NIP—530, Mometasonephate, Mizolastine, BP—294, Andlast, Auranofin, Ataribus Chin etc. are mentioned.
  • Examples of chemical mediator release inhibitors include sodium cromoglycate, tralast, amlexanox, levirinast, ibudilast, pemirolast potassium, dazanolast, nedocguchi mill, cromoglycato, israpafant, etc. .
  • histamine antagonist examples include ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, terfenadine, emedastine fumarate, epinastine hydrochloride, ebastine, cetirizine hydrochloride, olopatadine hydrochloride, oral latadine, and fensophenazine. Is mentioned.
  • thromboxane synthase inhibitor examples include ozadarel hydrochloride and imitrodast sodium.
  • thromboxane antagonist examples include seratrodast, ramatroban, domitroban force lucum hydrate, KT 2-962, and the like.
  • Th2 site force-in inhibitor examples include subrastast tosylate and the like.
  • steroidal drugs include topical drugs such as clobetasol propionate, diflorazone acetate, fluosinode, mometasone furanate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, diflurate Prednate, Pudesodium, Diflucortron valerate, Amsinode, Halcinode, Dexamethasone, Dexamethasone propionate, Dexamethasone valerate, Dexamethasone acetate, Hydrocortisone acetate, Hydrocortisone butyrate, Hydrocortisone butyrate propionate, Deprodo propionate , Prednisolone valerate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetate, flumethasone pivalate, alcromethasone propionate, clobetazo butyrate , Pre
  • xanthine derivatives include aminophylline, theophylline, doxophilin, synophylline, diprofylline, proxyphylline, choline theophylline and the like.
  • Examples of sympathomimetic drugs include epinephrine, ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, methoxyphenamine hydrochloride, isoproterenol sulfate, isoproterenol hydrochloride, orciprenaline sulfate, chlorprenalin hydrochloride, trimethoxy hydrochloride.
  • Parasympathetic nerve blockers include, for example, iprato oral pium bromide, furo oral pium bromide, oxytropium bromide, simetropium bromide, temiverine, tioto oral pium bromide, levatrope (UK-112166) and the like. Can be mentioned.
  • vaccine therapeutic agents include Paspart, Astremedin, Broncasma 'Berna, CS-560, and the like.
  • Examples of the gold preparation include gold sodium thiomalate.
  • Examples of the basic non-steroidal anti-inflammatory drug include thiaramide hydrochloride, tinolidine hydrochloride, epyrizole, emorphazone and the like.
  • Examples of 5-lipoxygenase inhibitors include zyleuton, docebenone, and pyripost.
  • Lipoxygenase activity ⁇ protein antagonists include, for example, MK-591, MK
  • Leukotriene synthesis inhibitors include, for example, auranofin, progouritacin maleate, L-674636, A-81834, UPA-780, A-93178, MK-886, REV-5
  • Examples of prostaglandins include PG receptor agonists.
  • Examples of PG receptors include PGE receptors (EP1, EP2, EP3, EP4), PGD receptors
  • DP DP, CRTH2
  • PGF receptor FP
  • PGI receptor IP
  • TX receptor TP
  • Antitussives include, for example, codine phosphate, dihydrocodine phosphate, oximetebanol, dextromethorphan hydrobromide, pentoxyberine citrate, dimemorphan phosphate, oxerazine oxalate, cloperastine, phosphate
  • Examples include benproperin, clofedanol hydrochloride, fominoben hydrochloride, noss force pin, tipimidine hibenzate, eprazinone hydrochloride, and chazenso extract.
  • Examples of expectorants include, for example, ammonia wikial, sodium bicarbonate, rhodium iodide, bromhexine hydrochloride, cherry bark extract, carbocystine, fudstein, ambroxol hydrochloride, ambroxol hydrochloride Methyl cysteine hydrochloride, acetyl cystine, L-ethyl cystine hydrochloride, and tyloxapol.
  • drugs for the prevention and Z or enhancement of the prevention and Z or treatment effect of the compound of the present invention on atopic dermatitis include, for example, steroid drugs, Non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, prostaglandins, antiallergic drugs, mediator release inhibitors, antihistamines, fuskolin preparations, phosphodiesterase inhibitors, cannapinoid 2 receptor agonists, etc. Can be mentioned.
  • drugs include anti-asthma drugs, inhaled steroids, inhaled j82 stimulants, methylxanthine asthma drugs, antiallergic drugs, anti-inflammatory drugs, anticholinergics, thromboxane antagonists, leukotrien antagonists, LTD4 antagonists , PAF antagonist, phosphodiesterase inhibitor, ⁇ 2 agonist, steroid drug, mediator release inhibitor, eosinophil chemotaxis, macrolide antibiotic, immunosuppressant, hyposensitization therapy (allergen) injection Etc.
  • allergen hyposensitization therapy
  • anti-asthma drugs examples include theophylline, pro-powered terol, ketotifen, and azelastine.
  • inhaled steroids examples include beclomethasone, fluchizone, budesonide and the like.
  • inhaled 13 2 stimulants examples include fenoterol, subtamol, formoterol, salmeterol and the like.
  • Examples of the methylxanthine asthma drug include theophylline.
  • antiallergic agents examples include ketotifen, terfenadine, azelastine, epinastin, suplatast, sodium cromoglycate and the like.
  • anti-inflammatory drug examples include diclofenac sodium, ibuprofen, indomethacin and the like.
  • anticholinergic agents examples include odorous platato-mouth pium, furto-mouth pium bromide, oxytropium bromide, tioto-mouth pium bromide and the like.
  • thromboxane antagonist examples include ozadarel, seratrodast and the like.
  • leukotriene antagonists include pranlukast, montelukast, zafuryl cast, and zylieuton.
  • macrolide antibiotics examples include erythromycin and roxithromycin. Can be mentioned.
  • immunosuppressive drug examples include cyclosporine, tacrolimus, FTY720, and the like.
  • Other drugs for the prevention and Z or therapeutic effect supplementation and Z or enhancement of hepatitis of the compounds of the present invention include, for example, liver hydrolyzate preparation, polyphosphatidylcholine, glycyrrhizin preparation, protoporphyrin sodium, Examples include ursodeoxycholic acid, steroid drugs, anticholinergic drugs, antacids, propagermanium, lipid peroxidase inhibitors, mitocondrial benzodiazepine receptor antagonists, and the like.
  • Other drugs for the supplementation and Z or enhancement of the prevention and Z or therapeutic effects of the compounds of the present invention on arthritis and rheumatoid arthritis include, for example, meta-oral proteinase inhibitors, immunosuppressants, non-steroidal drugs Anti-inflammatory drugs (NSAIDs), steroid drugs, prostaglandins, phosphodiesterase inhibitors, cannapinoid-2 receptor stimulants, disease-modifying anti-rheumatic drugs (slow-acting anti-rheumatic drugs), anti-inflammatory enzymes, cartilage protective drugs, T cell inhibition Drugs, TNFa inhibitors, prostaglandin synthase inhibitors, IL 6 inhibitors, interferon gamma agonists, IL 1 inhibitors and the like.
  • NSAIDs non-steroidal drugs
  • steroid drugs steroid drugs
  • prostaglandins phosphodiesterase inhibitors
  • cannapinoid-2 receptor stimulants cannapinoid-2 receptor stimulants
  • disease-modifying anti-rheumatic drugs slow-
  • Examples of other drugs for preventing and / or enhancing the effect of prevention and / or treatment of psoriasis with the compounds of the present invention include steroid drugs and vitamin D derivatives.
  • drugs for the prevention and moxibustion or therapeutic effect of rhinitis of the compounds of the present invention and for moxibustion or enhancement include, for example, antihistamines, mediator release inhibitors, thromboxane synthase inhibitors, thrombosis Leukotrien, a xantine receptor blocker
  • Receptor antagonists steroids, spider adrenergic receptors, xanthine derivatives, anticholins, prostaglandins, nitric oxide synthase inhibitors, beta adrenergic receptors
  • Stimulants phosphodiesterase inhibitors, cannapinoid-2 receptor stimulants and the like.
  • drugs for preventing and / or enhancing the effect of prevention and / or treatment of conjunctivitis on the compounds of the present invention include, for example, leukotriene receptor antagonists, antihistamines, mediator release inhibitors, Non-steroidal anti-inflammatory drugs, prostaglandins, These include steroid drugs, nitric oxide synthase inhibitors, and cannapinoid 2 receptor stimulants.
  • drugs for the prevention and Z or therapeutic effect complementation and Z or enhancement of the compound of the present invention for multiple sclerosis include, for example, immunosuppressants, cannapinoid 2 receptor stimulants and the like. It is done.
  • drugs for the prevention and Z or therapeutic effect supplementation and Z or enhancement of ulcerative colitis of the compounds of the present invention include, for example, mesalazine, salazosulfapyridine, drugs for gastrointestinal ulcer , Anticholinergic drugs, steroid drugs, 5-lipoxygenase inhibitors, antioxidants, LTB4 antagonists, local anesthetics, immunosuppressants, defense factor enhancers, MMP inhibitors, mitochondrial lubenzodiazepine receptor antagonists Etc.
  • drugs for the prevention and Z or therapeutic effect supplementation and Z or enhancement of diabetic complications of the compounds of the present invention include, for example, sulfo-urea hypoglycemic drugs, biguanide drugs, a Darcosidase inhibitor, Fast-acting insulin secretagogue, Insulin drug, PPAR agonist, Insulin sensitivity enhancer without PPAR agonist action, ⁇ 3 adrenergic receptor agonist, aldose reductase inhibitor, dipeptidyl Examples include peptidase IV inhibitors.
  • sulfonylurea-based hypoglycemic agent examples include acetohexamide, darivenclamide, daliclazide, glycloviramide, chlorpropamide, tolazamide, tolptamide, glimepiride and the like.
  • biguanide drugs include pformin hydrochloride and metformin hydrochloride.
  • Examples of the a-darcosidase inhibitor include carbose and voglibose.
  • Examples of fast-acting insulin secretagogues include nateglinide, repaglinide and the like.
  • PPAR agonists include, for example, pioglitazone, troglitazone, rosiglitazone, JTT
  • Insulin sensitivity-enhancing drugs that do not have PPAR agonist action include, for example, ONO 5816, YM-440 and the like.
  • Examples of the ⁇ 3 adrenergic receptor agonist include AJ9677, L750355, CP33164 8, and the like.
  • aldose reductase inhibitors examples include epalrestat, fidarestat, xenarestat, and the like.
  • agents for the prevention of cancer (malignant tumors) and cancer metastasis of the compounds of the present invention and for the supplementation and enhancement of acupuncture or therapeutic effects include, for example, anticancer agents (eg, acupuncture inhibitors, alkylation) Drugs (eg, cyclophosphamide, melphalan, thiotepa, mitomycin C, busulfan, procarbazine hydrochloride, etc.), antimetabolites (eg, methotrexate, mercaptopurine, azathioprine, fluorouracil, tegafur, cytarabine, azaserin, etc.), Antibiotics (eg, mitomycin C, bleomycin, pepromycin, doxorubicin hydrochloride, aclarubicin, daunorubicin, actinomycin D, etc.), mitotic inhibitors, platinum complexes (eg, cisplatin), plant-derived antineoplastic agents (eg,
  • Biologics that perform T cell activity eg, anti-CTLA-4 antibody, anti-PD-1) Antibodies
  • angiogenesis inhibitors eg, bevacizumab, pegaptan3 ⁇ 4, SU-6668, vatalan3 ⁇ 4, ranib izumab, sorafenib
  • SU-11248, Neobasstat etc.
  • Other drugs for prevention and Z or therapeutic effect supplementation and Z or enhancement of immune diseases for example, autoimmune diseases, transplanted organ rejection, etc.
  • immune diseases for example, autoimmune diseases, transplanted organ rejection, etc.
  • drugs for prevention and Z or therapeutic effect supplementation and Z or enhancement of immune diseases include, for example, immunosuppressive drugs (For example, cyclosporine, tacrolimus, FTY720, etc.).
  • Other drugs for the prevention and Z or therapeutic effect supplementation and Z or enhancement of dementia such as Alzheimer-type senile dementia of the compound of the present invention include, for example, Examples include cetylcholinesterase inhibitors, nicotine receptor modulators, cerebral circulation metabolism improvers, monoamine oxidase inhibitors, vitamin E, and aldose reductase inhibitors.
  • agents for the prevention and Z or therapeutic effect complementation and Z or enhancement of epilepsy of the compounds of the present invention include, for example, quitoin, trimetadione, ethosuximide, carbamazepine, phenobarbital, primidone, acetazolamide Sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
  • Other drugs for the prevention and Z or therapeutic effect supplementation and Z or enhancement of arteriosclerosis of the compounds of the present invention include, for example, HMG-CoA reductase inhibitors, fibrates, probucol preparations, Examples include ion exchange resin, EPA preparation, nicotinic acid preparation, MTP inhibitor, other anti-high cholesterol drugs, and EDG-2 antagonists.
  • cytopower-ins and various growth factors such as various CSFs (for example, G— CSF, GM-CSF, etc.), various interleukins (eg IL-3, 6, 7, 11, 12, etc.), EPO, TPO, SCF, FLT3 ligand, MIP-1a, etc.
  • CSFs for example, G— CSF, GM-CSF, etc.
  • interleukins eg IL-3, 6, 7, 11, 12, etc.
  • EPO EPO
  • TPO TPO
  • SCF FLT3 ligand
  • MIP-1a etc.
  • agents for supplementing and enhancing Z or augmentation of the prevention and Z or therapeutic effects of the compounds of the present invention on retinopathy include, for example, angiogenesis inhibitors (eg, bevacizumab, Geptabu (pegaptanib), SU-6668, butalarab (vatalanib) ⁇ rabitizumab (sorafenib), SU-11248, neovastat (neovastat) and the like.
  • angiogenesis inhibitors eg, bevacizumab, Geptabu (pegaptanib), SU-6668, butalarab (vatalanib) ⁇ rabitizumab (sorafenib), SU-11248, neovastat (neovastat) and the like.
  • the compound of the present invention is safe and has low toxicity, it can be used, for example, in mammals other than humans (for example, rats, mice, rabbits, hidges, pigs, mice, cats, dogs, monkeys, etc.). In contrast, it can be administered.
  • composition comprising the compound of the present invention or a combination agent of the compound of the present invention and another drug for the above-mentioned purpose, it is usually systemically or locally, orally or parenterally. Be administered.
  • the dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually once per adult, in the range of lng to lOOOmg once a day several times per day Administered in the range of O. lng to lOOmg once per adult It can be administered parenterally once to several times a day, or it can be administered intravenously in the range of 1 to 24 hours per day.
  • the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient, or administration beyond the range may be necessary.
  • a pharmaceutical composition comprising the compound of the present invention or a combination agent of the compound of the present invention and another drug
  • a solid preparation for internal use for oral administration a liquid preparation for internal use, and a parenteral administration Used as injections, external preparations, suppositories, eye drops, nasal drops, inhalants, etc. for administration
  • Solid preparations for internal use for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • one or more active substances may be used as they are as force or excipients (latatose, mannitol, glucose, microcrystalline cellulose, denpun, etc.), binders (hydroxypropyl). Cellulose, polypyrrole pyrrolidone, magnesium metasilicate aluminate, etc.), disintegrating agents (such as calcium calcium glycolate), lubricants (magnesium stearate, etc.), stabilizers, solubilizers (glutamic acid, aspartic acid, etc.) Etc., and formulated into a conventional method.
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of substances that can be absorbed such as gelatin.
  • Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • a solution one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (purified water, ethanol or a mixture thereof).
  • this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • External dosage forms for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, Including eye drops and nasal drops. These contain one or more active substances and are prepared by known methods or commonly used formulations.
  • An ointment is produced by a known or commonly used formulation. For example, it is prepared by grinding or melting one or more active substances in a base. The ointment base may be selected from known or commonly used strengths.
  • higher fatty acids or higher fatty acid esters such as adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester), waxes ( Beeswax, whale wax, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.), carbonized Hydrogen (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oil (castor oil, olive oil, etc.) Bed oil, sesame oil, turpentine oil etc.),
  • the gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base.
  • the gel base may be selected from known or commonly used forces. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.) , Surfactants (polyethylenestearic acid monopolyacrylate, etc.), gums, water, absorption promoters, anti-rash agents, or a mixture of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Creams are produced by known or commonly used formulations. For example, it is prepared by melting or emulsifying one or more active substances in a base.
  • the cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), Emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, anti-rash agents, selected one or a mixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.
  • the poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support.
  • the poultice base is selected from known or commonly used ones. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (strongline, zinc oxide, talc, calcium) , Magnesium, etc.), water, solubilizers, tackifiers, anti-rash agents, selected one or a mixture of two or more. In addition, preservatives, antioxidants, flavoring agents and the like may be included.
  • the patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support.
  • the base for patch is selected from known or commonly used ones. For example, one selected from high molecular weight bases, fats and oils, higher fatty acids, tackifiers, and rash prevention agents may be used alone or in admixture of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the liniment is produced by a known or commonly used formulation.
  • one or more active substances are dissolved in water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. alone or in two or more types, It is prepared by suspending or emulsifying. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Sprays, inhalants, and sprays, other than commonly used diluents are buffers that provide isotonicity with stabilizers such as sodium bisulfite, such as sodium chloride salt, kenic acid. Is sodium, or contains isotonic agents such as citrate.
  • injections for parenteral administration include all injections, and also include drops.
  • injections for parenteral administration include all injections, and also include drops.
  • intramuscular injection subcutaneous injection, intradermal injection, intraarterial injection, intravenous injection, intraperitoneal injection, spinal cavity injection, glass Note to the body Including injection, intravenous drip, etc.
  • Injectables for parenteral administration include solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent at the time of use.
  • An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
  • this injection may contain stabilizers, solubilizers (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. Good.
  • Ophthalmic solutions for parenteral administration include ophthalmic solutions, suspension-type ophthalmic solutions, emulsion-type ophthalmic solutions, in-use dissolving ophthalmic solutions, and eye ointments.
  • These eye drops are prepared according to a known method.
  • one or more active substances are used by dissolving, suspending or emulsifying them in a solvent.
  • a solvent for example, sterilized purified water, physiological saline, other aqueous solvents or non-aqueous preparations for injection (for example, vegetable oil) and the like and combinations thereof are used.
  • Eye drops include isotonic agents (salt sodium, concentrated glycerin, etc.), buffering agents (sodium phosphate, sodium acetate, etc.), surfactants (polysorbate 80 (trade name), polyoxyl 40 stearate, Polyoxyethylene hydrogenated castor oil, etc.), stabilizers (sodium taenoate, sodium edetate, etc.), preservatives (salt benzalcoum, parabens, etc.) etc. Also good. These are prepared by the sterilization power and aseptic operation method in the final step. In addition, an aseptic solid preparation, for example, a freeze-dried product, can be produced and used by dissolving in sterilized or sterilized sterile purified water or other solvent before use.
  • isotonic agents salt sodium, concentrated glycerin, etc.
  • buffering agents sodium phosphate, sodium acetate, etc.
  • surfactants polysorbate 80 (trade name), polyoxyl 40 stearate, Polyoxyethylene hydrogen
  • Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are dissolved or suspended in water or other suitable medium at the time of use. It may be a form to use.
  • inhalants are produced according to known methods.
  • preservatives salts, benzalcoum, parabens, etc.
  • coloring agents for example, in the case of inhalation solutions, preservatives (salts, benzalcoum, parabens, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), isotonic agents ( (Salt sodium salt, concentrated glycerin, etc.), thickener (cariboxyvinyl polymer, etc.), absorption enhancer, etc., as necessary.
  • lubricants stearic acid and its salts, etc.
  • binders denpun, dextrin, etc.
  • excipients lactose, cellulose, etc.
  • coloring agents preservatives (Salt-bensal-comb, noben, etc.), absorption enhancer, etc., as necessary.
  • a nebulizer (one atomizer or one nebulizer) is usually used when administering an inhalation solution, and an inhalation administration device for a powder drug is usually used when administering an inhalable powder.
  • compositions for parenteral administration include suppositories for rectal administration, pessaries for intravaginal administration, etc., which contain one or more active substances and are prescribed by conventional methods Is included.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I), un sel, un N-oxyde ou un solvate dudit composé et un promédicament du composé, du sel, du N-oxyde ou du solvate. (I) dans laquelle chaque symbole est tel que défini dans le mémoire descriptif. Le composé a un effet antagoniste de CXCR4 et il est utilisable en tant qu'agent prophylactique et/ou thérapeutique pour une maladie induite par CXCR4 telle qu'une maladie inflammatoire/immunitaire (par exemple la polyarthrite rhumatoïde, l'arthrite, la rétinopathie, le fibrome pulmonaire, le rejet du greffon), une maladie allergique, une maladie infectieuse (par exemple l'infection par le virus de l'immunodéficience humaine, le syndrome d'immunodéficience acquise), une maladie mentale/neurologique, une maladie cérébrale, une maladie cardiovasculaire, une maladie métabolique, une maladie cancéreuse (par exemple le cancer, la métastase du cancer). Ledit agent est également utilisable en médecine de régénération.
PCT/JP2007/059960 2006-05-16 2007-05-15 Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé WO2007132846A1 (fr)

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US12/301,194 US8618122B2 (en) 2006-05-16 2007-05-15 Compound having acidic group which may be protected, and use thereof
JP2008515563A JP5257068B2 (ja) 2006-05-16 2007-05-15 保護されていてもよい酸性基を含有する化合物およびその用途
EP07743395A EP2042503B1 (fr) 2006-05-16 2007-05-15 Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé

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JP2006136925 2006-05-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2055705A1 (fr) * 2006-07-31 2009-05-06 Ono Pharmaceutical CO., LTD. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
WO2010147094A1 (fr) * 2009-06-16 2010-12-23 小野薬品工業株式会社 Composé ayant un groupe cyclique à liaison spiro et son utilisation

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4710606B2 (ja) * 2003-04-18 2011-06-29 小野薬品工業株式会社 スピロピペリジン化合物およびその医薬用途
WO2006022454A1 (fr) * 2004-08-27 2006-03-02 Ono Pharmaceutical Co., Ltd Composé contenant un groupe basique et utilisation
PL1961744T3 (pl) * 2005-11-18 2013-09-30 Ono Pharmaceutical Co Związek zawierający grupę zasadową oraz jego zastosowanie
JP5257068B2 (ja) 2006-05-16 2013-08-07 小野薬品工業株式会社 保護されていてもよい酸性基を含有する化合物およびその用途
RU2498798C2 (ru) * 2008-01-09 2013-11-20 Моликьюлар Инсайт Фармасьютикалз, Инк. Ингибиторы карбоангидразы iх
WO2010065899A2 (fr) 2008-12-05 2010-06-10 Molecular Insight Pharmaceuticals, Inc. Complexes de technétium- et rhénium-bis (hétéroaryles) et leurs procédés d'utilisation
US8465725B2 (en) 2009-06-15 2013-06-18 Molecular Insight Pharmaceuticlas, Inc. Process for production of heterodimers of glutamic acid
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
EP2670752B1 (fr) 2011-02-02 2016-03-16 Vertex Pharmaceuticals Incorporated Amides de pipéridine spirocyclique-pyrrolopyrazine en tant que modulateurs de canaux ioniques
EP2675812B1 (fr) 2011-02-18 2017-08-30 Vertex Pharmaceuticals Incorporated Amides de pipéridine spirocyclique chromanique en tant que modulateurs des canaux ioniques
CN103517910B (zh) 2011-03-14 2016-12-14 沃泰克斯药物股份有限公司 作为离子通道调节剂的吗啉-螺环哌啶酰胺
WO2013103813A1 (fr) 2012-01-06 2013-07-11 Molecular Insight Pharmaceuticals Complexe métalliques de poly (carboxyl) amine contenant des ligands ayant une affinité pour l'anhydrase carbonique ix
SG11201505477TA (en) 2013-01-14 2015-08-28 Molecular Insight Pharm Inc Triazine based radiopharmaceuticals and radioimaging agents
CA2909938A1 (fr) * 2013-04-22 2014-10-30 Abbvie Inc. Thiazoles et utilisations de ceux-ci

Citations (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB427857A (en) 1934-08-02 1935-05-01 Newsum Sons & Company Ltd H A new or improved system of construction for skeleton structures, particularly vehicle body frames and door frames
WO1999004794A1 (fr) 1997-07-25 1999-02-04 Merck & Co., Inc. Amines cycliques modulant l'activite des recepteurs de chimiokines
WO1999007351A2 (fr) 1997-08-07 1999-02-18 Zeneca Limited Composes chimiques
DE19837386A1 (de) 1997-08-18 1999-02-25 Hoffmann La Roche CCR-3-Rezeptorantagonisten
WO1999017773A1 (fr) 1997-10-07 1999-04-15 Smithkline Beecham Corporation Composes et procedes
WO1999032100A2 (fr) 1997-12-19 1999-07-01 Takeda Chemical Industries, Ltd. Composition pharmaceutique antagoniste de ccr5 et contenant un derive d'anilide
WO1999040913A1 (fr) 1998-02-17 1999-08-19 Astrazeneca Uk Limited Composes chimiques
WO1999055324A1 (fr) 1998-04-27 1999-11-04 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO1999055330A1 (fr) 1998-04-27 1999-11-04 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000004003A1 (fr) 1998-07-14 2000-01-27 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000006153A1 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Propenamides tenant lieu de modulateurs de ccr5
WO2000006085A2 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Composes et procedes
WO2000006146A1 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Composes d'anilide substitues et methodes associees
WO2000010965A2 (fr) 1998-08-20 2000-03-02 Takeda Chemical Industries, Ltd. Sels d'ammonium quaternaire et leur utilisation
WO2000021916A1 (fr) 1998-10-15 2000-04-20 Takeda Chemical Industries, Ltd. Procede de preparation de derives d'amine
WO2000027800A1 (fr) 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000027835A1 (fr) 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000027843A1 (fr) 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr3-3
WO2000029377A1 (fr) 1998-11-17 2000-05-25 F. Hoffmann-La Roche Ag Antagonistes iii du recepteur 4-aroyl-piperidin-ccr-3
WO2000031032A1 (fr) 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de derives de pyrrolidine-ccr-3
WO2000031033A1 (fr) 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de piperidine ccr-3
WO2000034278A1 (fr) 1998-12-04 2000-06-15 Toray Industries, Inc. Derives triazolo, et inhibiteurs de chimiokines contenant ces derives comme ingredient actif
WO2000035451A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035454A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035453A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035877A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Piperidines heterocycliques utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035449A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035876A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Heterocycles 2-substitues-4-azote utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035452A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
EP1013276A1 (fr) 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalcanes comme modulateurs de CCR5
WO2000037455A1 (fr) 1998-12-21 2000-06-29 Takeda Chemical Industries, Ltd. Derives de benzothiepin-anilide, production et utilisation comme antagoniste de ccr-5
WO2000039125A1 (fr) 1998-12-23 2000-07-06 Pfizer Limited Piperidines utilises comme modulateurs de ccr5
WO2000038580A1 (fr) 1998-12-30 2000-07-06 Pharmasonics, Inc. Catheter ultrasonore therapeutique permettant l'administration d'une dose d'energie uniforme
WO2000040239A1 (fr) 1998-12-30 2000-07-13 Smithkline Beecham Corporation Composes et procedes
WO2000041685A1 (fr) 1999-01-19 2000-07-20 Smithkline Beecham Corporation Antagonistes des recepteurs ccr-3
WO2000042045A2 (fr) 1999-01-13 2000-07-20 Warner-Lambert Company Heterocycles fonctionnalises en tant que modulateurs des recepteurs de chimiokines
US6093324A (en) 1996-08-07 2000-07-25 Csl Limited Purification of immunoglobulins
WO2000042852A1 (fr) 1999-01-25 2000-07-27 Smithkline Beecham Corporation Composes et procedes
WO2000046196A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole et leur utilisation comme antagonistes vis-a-vis de la proteine 1 ayant un chimiotactisme positif sur les monocytes (mcp-1)
WO2000046199A2 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Composes chimiques
WO2000046195A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole anti-inflammatoires
WO2000046198A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole, anti-inflammatoires
WO2000046197A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole et leur utilisation comme antagonistes vis-a-vis du recepteur mcp-1
WO2000051607A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite recepteur des chimiokines, a base de 3-cyclopropyle et 3-cyclobutyle
WO2000051610A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite de recepteurs de chemokine a base de pyrrolidine
WO2000051608A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite recepteur des chimiokines, a base de 3-thienyle et 3-furanyle pyrrolidine
WO2000051609A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite recepteur des chimiokines, a base de pyrrolidine a substitution 3-alkyle
WO2000053172A1 (fr) 1999-03-08 2000-09-14 Smithkline Beecham Corporation Antagonistes du récepteur ccr-3
WO2000053175A1 (fr) 1999-03-10 2000-09-14 Smithkline Beecham Corporation Composés et méthodes
WO2000053600A1 (fr) 1999-03-11 2000-09-14 Banyu Pharmaceutical Co., Ltd. Derives piperidiniques
WO2000056729A1 (fr) 1999-03-24 2000-09-28 Anormed Inc. Composes heterocycliques se liant aux recepteurs de chimiokine
WO2000058305A1 (fr) 1999-03-26 2000-10-05 Astrazeneca Ab Nouveaux composes
WO2000059502A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Pyrrolidines modulateurs de l'activite du recepteur de chimiokine
WO2000059497A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Modulateurs de pyrrolidine de l'activite du recepteur des chimiokines
WO2000059503A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Modulateurs de pyrrolidine de l'activite du recepteur des chimiokines
WO2000059498A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Modulateurs de pyrrolidine de l'activite du recepteur des chimiokines
WO2000062814A2 (fr) 1999-04-21 2000-10-26 Children's Hospital Medical Center Ciblage pharmaceutique intracellulaire
JP2000309598A (ja) 1999-02-25 2000-11-07 Takeda Chem Ind Ltd 多剤結合型新規化合物、その製造法および用途
WO2000066559A1 (fr) 1999-05-04 2000-11-09 Schering Corporation Derives de piperidine faisant office d'antagonistes ccr5
WO2000066112A1 (fr) 1999-05-03 2000-11-09 Smithkline Beecham Corporation Antagonistes du recepteur cxcr-4 et mimetiques de thrombopoietine
WO2000066558A1 (fr) 1999-05-04 2000-11-09 Schering Corporation Derives de piperazine faisant office d'antagonistes ccr5
WO2000066141A2 (fr) 1999-05-04 2000-11-09 Schering Corporation Pharmacotherapie anti-vih utilisant une combinaison d'un peg-interferon-alpha et d'un antagoniste ccr5
WO2000066551A1 (fr) 1999-04-28 2000-11-09 Takeda Chemical Industries, Ltd. Composes d'amides cycliques, leurs procedes de preparation et d'utilisation
WO2000068203A1 (fr) 1999-05-07 2000-11-16 Takeda Chemical Industries, Ltd. Composes cycliques et leurs utilisations
WO2000069432A1 (fr) 1999-05-18 2000-11-23 Teijin Limited Moyens de traitement et de prevention contre les maladies associees a des chimiokines
WO2000069815A1 (fr) 1999-05-13 2000-11-23 Teijin Limited Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament
WO2000073327A1 (fr) 1999-05-27 2000-12-07 Celltek Biotechnologies Inc. Antagonistes ccr3 de recepteurs de chimiokine
WO2000076933A2 (fr) 1999-06-10 2000-12-21 Ergon, Inc. Compositions de platre resistantes a l'eau
WO2001009088A1 (fr) 1999-07-28 2001-02-08 Kirin Beer Kabushiki Kaisha Derives d'uree utilises comme inhibiteurs du recepteur ccr-3
WO2002030357A2 (fr) 2000-10-11 2002-04-18 Chemocentryx, Inc. Composes et procedes servant a moduler la fonction de ccr4
WO2002030358A2 (fr) 2000-10-11 2002-04-18 Tularik Inc. Modulation de fonction de ccr4
WO2003029218A1 (fr) * 2001-09-28 2003-04-10 Kureha Chemical Industry Company, Limited Compose azote et utilisation correspondante
WO2004024697A1 (fr) 2002-09-11 2004-03-25 Kureha Chemical Industry Company, Limited Composes amines et leurs utilisation
WO2004052862A1 (fr) 2002-12-10 2004-06-24 Ono Pharmaceutical Co., Ltd. Composes heterocycliques contenant de l'azote et leur utilisation medicale
WO2005085209A1 (fr) 2004-03-10 2005-09-15 Kureha Corporation Composé aminé basique et son usage
WO2006020415A1 (fr) 2004-08-02 2006-02-23 Smithkline Beecham Corporation Composes chimiques
WO2006020891A2 (fr) 2004-08-13 2006-02-23 Anormed Inc. Combinaisons de chimiokines pour mobiliser des cellules progenitrices/souches
WO2006022454A1 (fr) 2004-08-27 2006-03-02 Ono Pharmaceutical Co., Ltd Composé contenant un groupe basique et utilisation
WO2006023400A2 (fr) 2004-08-16 2006-03-02 Smithkline Beecham Corporation Composes chimiques
WO2006028896A2 (fr) 2004-09-02 2006-03-16 Smithkline Beecham Corporation Composes chimiques
US20060069122A1 (en) 2004-09-29 2006-03-30 Anormed Inc. Chemokine-binding heterocyclic compound salts, and methods of use thereof
WO2006034001A2 (fr) 2004-09-16 2006-03-30 Bristol-Myers Squibb Company Procedes de traitement de l'infection par vih
WO2006036816A2 (fr) 2004-09-24 2006-04-06 Smithkline Beecham Corporation Composes chimiques
WO2006048862A2 (fr) 2004-10-31 2006-05-11 Yeda Research And Development Co.Ltd. Utilisation d'une protease ou d'un inhibiteur de protease pour la preparation de medicaments
WO2006074426A2 (fr) 2005-01-07 2006-07-13 Emory University Antagonistes de cxcr4 pour le traitement de l'infection due au vih
JP2006188445A (ja) 2005-01-05 2006-07-20 Ono Pharmaceut Co Ltd 含窒素複素環化合物およびその医薬用途
WO2006076131A2 (fr) 2004-12-17 2006-07-20 Smithkline Beecham Corporation Composes chimiques
US20060160860A1 (en) 2005-01-20 2006-07-20 Taigen Biotechnology Synthesis of polyamine compounds
WO2006090853A1 (fr) 2005-02-25 2006-08-31 Ono Pharmaceutical Co., Ltd. Composé hétérocyclique azoté et utilisation médicale de celui-ci
WO2006096444A2 (fr) 2005-03-04 2006-09-14 Smithkline Beecham Corporation Composes chimiques
WO2006117011A1 (fr) 2005-05-02 2006-11-09 Polyphor Ltd. Conjugues colorants de peptidomimetiques fixes sur matrice
US20060281712A1 (en) 2005-06-14 2006-12-14 Chi-Feng Yen Pyrimidine compounds
WO2007008539A2 (fr) 2005-07-11 2007-01-18 Smithkline Beecham Corporation Composes chimiques
WO2007022385A2 (fr) 2005-08-18 2007-02-22 Novartis Ag Molécules se liant au cxcr4
WO2007027999A2 (fr) 2005-08-31 2007-03-08 Smithkline Beecham Corporation Composes chimiques

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3301857A (en) * 1963-08-26 1967-01-31 Hoffmann La Roche Spiro
JPS565756B2 (fr) 1972-06-03 1981-02-06
JPS5516167B2 (fr) 1972-11-10 1980-04-30
JPS5815979A (ja) 1981-07-11 1983-01-29 Kyowa Hakko Kogyo Co Ltd 新規なピペリジン誘導体およびその製造法
JPH0418092A (ja) 1990-05-09 1992-01-22 Yamanouchi Pharmaceut Co Ltd スピロ化合物またはその塩
AU7186494A (en) 1993-07-02 1995-01-24 Bayer Aktiengesellschaft Substituted spiroheterocyclic 1h-3-arylpyrrolidine-2,4-dione derivatives, methods of preparing them and their use as pest-control agents
US5534537A (en) * 1995-03-29 1996-07-09 Merck & Co., Inc. Prodrugs of inhibitors of farnesyl-protein transferase
NZ320963A (en) * 1995-09-29 1999-08-30 Lilly Co Eli Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
AU5803398A (en) 1996-12-13 1998-07-03 Merck & Co., Inc. Spiro-substituted azacycles as modulators of chemokine receptor activity
US5962462A (en) * 1996-12-13 1999-10-05 Merck & Co., Inc. Spiro-substituted azacycles as modulators of chemokine receptor activity
JPH11321508A (ja) 1998-03-18 1999-11-24 Denso Corp エアバッグ及びその製造方法
TWI279402B (en) 1999-08-20 2007-04-21 Banyu Pharma Co Ltd Spiro compounds having NPY antagonistic activities and agents containing the same
US6803372B2 (en) 1999-08-20 2004-10-12 Banyu Pharmaceutical Co., Ltd. Spiro compounds
JP3553560B2 (ja) 1999-08-20 2004-08-11 萬有製薬株式会社 新規スピロ化合物
JP2003507424A (ja) 1999-08-26 2003-02-25 ブリストル−マイヤーズ スクイブ カンパニー Ｎｐｙアンタゴニスト：スピロイソキノリノン誘導体
EP1302462A4 (fr) * 2000-07-17 2007-07-18 Takeda Pharmaceutical Derives de sulfonate, procede de production et utilisation de ces derives
AU2001283502A1 (en) * 2000-07-26 2002-02-05 Livewave, Inc. Methods and systems for networked camera control
JP4101053B2 (ja) 2000-08-10 2008-06-11 田辺三菱製薬株式会社 プロリン誘導体及びその医薬用途
US6835731B2 (en) 2000-09-15 2004-12-28 Anormed, Inc. Chemokine receptor binding heterocyclic compounds
IL154227A0 (en) 2000-09-15 2003-07-31 Anormed Inc Chemokine receptor binding heterocyclic compounds
EP1619194A3 (fr) 2001-03-19 2006-06-07 Ono Pharmaceutical Co., Ltd. Dérivés de triazaspiro¬5.5|undécane et le composition pharmaceutique qui les comprend comme ingrédient actif
JP2002348288A (ja) 2001-05-28 2002-12-04 Ono Pharmaceut Co Ltd スピロ複素環誘導体およびそれらを有効成分とする薬剤
GB0121033D0 (en) 2001-08-30 2001-10-24 Novartis Ag Organic compounds
JP2005089298A (ja) 2001-09-18 2005-04-07 Japan Tobacco Inc ナフタレン化合物及びその医薬用途
US7354932B2 (en) * 2001-12-21 2008-04-08 Anormed, Inc. Chemokine receptor binding heterocyclic compounds with enhanced efficacy
KR20040068339A (ko) 2001-12-21 2004-07-30 아노르메드 인코포레이티드 효능이 강화된 케모카인 수용체 결합 헤테로사이클릭 화합물
WO2003057698A2 (fr) 2001-12-28 2003-07-17 Acadia Pharmaceuticals, Inc. Composes spiroazacycliques utilises comme modulateurs du recepteur de monoamine
PL1961744T3 (pl) * 2005-11-18 2013-09-30 Ono Pharmaceutical Co Związek zawierający grupę zasadową oraz jego zastosowanie
JP5257068B2 (ja) 2006-05-16 2013-08-07 小野薬品工業株式会社 保護されていてもよい酸性基を含有する化合物およびその用途
KR20090128401A (ko) * 2007-03-01 2009-12-15 파나소닉 주식회사 발광 표시 장치, 플라즈마 표시 장치 및 형광체 입자
TW201103540A (en) * 2009-06-16 2011-02-01 Ono Pharmaceutical Co Compound having spiro-linked cyclic group and uses thereof
US7883991B1 (en) * 2010-02-18 2011-02-08 Taiwan Semiconductor Manufacturing Company, Ltd. Temporary carrier bonding and detaching processes

Patent Citations (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB427857A (en) 1934-08-02 1935-05-01 Newsum Sons & Company Ltd H A new or improved system of construction for skeleton structures, particularly vehicle body frames and door frames
US6093324A (en) 1996-08-07 2000-07-25 Csl Limited Purification of immunoglobulins
WO1999004794A1 (fr) 1997-07-25 1999-02-04 Merck & Co., Inc. Amines cycliques modulant l'activite des recepteurs de chimiokines
WO1999007351A2 (fr) 1997-08-07 1999-02-18 Zeneca Limited Composes chimiques
DE19837386A1 (de) 1997-08-18 1999-02-25 Hoffmann La Roche CCR-3-Rezeptorantagonisten
WO1999017773A1 (fr) 1997-10-07 1999-04-15 Smithkline Beecham Corporation Composes et procedes
WO1999032100A2 (fr) 1997-12-19 1999-07-01 Takeda Chemical Industries, Ltd. Composition pharmaceutique antagoniste de ccr5 et contenant un derive d'anilide
WO1999040913A1 (fr) 1998-02-17 1999-08-19 Astrazeneca Uk Limited Composes chimiques
WO1999055324A1 (fr) 1998-04-27 1999-11-04 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO1999055330A1 (fr) 1998-04-27 1999-11-04 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000004003A1 (fr) 1998-07-14 2000-01-27 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000006153A1 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Propenamides tenant lieu de modulateurs de ccr5
WO2000006085A2 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Composes et procedes
WO2000006146A1 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Composes d'anilide substitues et methodes associees
WO2000010965A2 (fr) 1998-08-20 2000-03-02 Takeda Chemical Industries, Ltd. Sels d'ammonium quaternaire et leur utilisation
WO2000021916A1 (fr) 1998-10-15 2000-04-20 Takeda Chemical Industries, Ltd. Procede de preparation de derives d'amine
WO2000027800A1 (fr) 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000027835A1 (fr) 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr-3
WO2000027843A1 (fr) 1998-11-09 2000-05-18 Smithkline Beecham Corporation Antagonistes du recepteur ccr3-3
WO2000029377A1 (fr) 1998-11-17 2000-05-25 F. Hoffmann-La Roche Ag Antagonistes iii du recepteur 4-aroyl-piperidin-ccr-3
WO2000031032A1 (fr) 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de derives de pyrrolidine-ccr-3
WO2000031033A1 (fr) 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de piperidine ccr-3
WO2000034278A1 (fr) 1998-12-04 2000-06-15 Toray Industries, Inc. Derives triazolo, et inhibiteurs de chimiokines contenant ces derives comme ingredient actif
WO2000035451A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035454A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035453A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035877A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Piperidines heterocycliques utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035449A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035876A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Heterocycles 2-substitues-4-azote utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000035452A1 (fr) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
WO2000037455A1 (fr) 1998-12-21 2000-06-29 Takeda Chemical Industries, Ltd. Derives de benzothiepin-anilide, production et utilisation comme antagoniste de ccr-5
EP1013276A1 (fr) 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalcanes comme modulateurs de CCR5
WO2000039125A1 (fr) 1998-12-23 2000-07-06 Pfizer Limited Piperidines utilises comme modulateurs de ccr5
WO2000038580A1 (fr) 1998-12-30 2000-07-06 Pharmasonics, Inc. Catheter ultrasonore therapeutique permettant l'administration d'une dose d'energie uniforme
WO2000040239A1 (fr) 1998-12-30 2000-07-13 Smithkline Beecham Corporation Composes et procedes
WO2000042045A2 (fr) 1999-01-13 2000-07-20 Warner-Lambert Company Heterocycles fonctionnalises en tant que modulateurs des recepteurs de chimiokines
WO2000041685A1 (fr) 1999-01-19 2000-07-20 Smithkline Beecham Corporation Antagonistes des recepteurs ccr-3
WO2000042852A1 (fr) 1999-01-25 2000-07-27 Smithkline Beecham Corporation Composes et procedes
WO2000046196A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole et leur utilisation comme antagonistes vis-a-vis de la proteine 1 ayant un chimiotactisme positif sur les monocytes (mcp-1)
WO2000046199A2 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Composes chimiques
WO2000046195A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole anti-inflammatoires
WO2000046198A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole, anti-inflammatoires
WO2000046197A1 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Derives d'indole et leur utilisation comme antagonistes vis-a-vis du recepteur mcp-1
JP2000309598A (ja) 1999-02-25 2000-11-07 Takeda Chem Ind Ltd 多剤結合型新規化合物、その製造法および用途
WO2000051608A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite recepteur des chimiokines, a base de 3-thienyle et 3-furanyle pyrrolidine
WO2000051610A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite de recepteurs de chemokine a base de pyrrolidine
WO2000051607A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite recepteur des chimiokines, a base de 3-cyclopropyle et 3-cyclobutyle
WO2000051609A1 (fr) 1999-03-02 2000-09-08 Merck & Co., Inc. Modulateurs de l'activite recepteur des chimiokines, a base de pyrrolidine a substitution 3-alkyle
WO2000053172A1 (fr) 1999-03-08 2000-09-14 Smithkline Beecham Corporation Antagonistes du récepteur ccr-3
WO2000053175A1 (fr) 1999-03-10 2000-09-14 Smithkline Beecham Corporation Composés et méthodes
WO2000053600A1 (fr) 1999-03-11 2000-09-14 Banyu Pharmaceutical Co., Ltd. Derives piperidiniques
WO2000056729A1 (fr) 1999-03-24 2000-09-28 Anormed Inc. Composes heterocycliques se liant aux recepteurs de chimiokine
WO2000058305A1 (fr) 1999-03-26 2000-10-05 Astrazeneca Ab Nouveaux composes
WO2000059502A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Pyrrolidines modulateurs de l'activite du recepteur de chimiokine
WO2000059497A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Modulateurs de pyrrolidine de l'activite du recepteur des chimiokines
WO2000059503A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Modulateurs de pyrrolidine de l'activite du recepteur des chimiokines
WO2000059498A1 (fr) 1999-04-06 2000-10-12 Merck & Co., Inc. Modulateurs de pyrrolidine de l'activite du recepteur des chimiokines
WO2000062814A2 (fr) 1999-04-21 2000-10-26 Children's Hospital Medical Center Ciblage pharmaceutique intracellulaire
WO2000066551A1 (fr) 1999-04-28 2000-11-09 Takeda Chemical Industries, Ltd. Composes d'amides cycliques, leurs procedes de preparation et d'utilisation
WO2000066112A1 (fr) 1999-05-03 2000-11-09 Smithkline Beecham Corporation Antagonistes du recepteur cxcr-4 et mimetiques de thrombopoietine
WO2000066559A1 (fr) 1999-05-04 2000-11-09 Schering Corporation Derives de piperidine faisant office d'antagonistes ccr5
WO2000066558A1 (fr) 1999-05-04 2000-11-09 Schering Corporation Derives de piperazine faisant office d'antagonistes ccr5
WO2000066141A2 (fr) 1999-05-04 2000-11-09 Schering Corporation Pharmacotherapie anti-vih utilisant une combinaison d'un peg-interferon-alpha et d'un antagoniste ccr5
WO2000068203A1 (fr) 1999-05-07 2000-11-16 Takeda Chemical Industries, Ltd. Composes cycliques et leurs utilisations
WO2000069815A1 (fr) 1999-05-13 2000-11-23 Teijin Limited Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament
WO2000069432A1 (fr) 1999-05-18 2000-11-23 Teijin Limited Moyens de traitement et de prevention contre les maladies associees a des chimiokines
WO2000073327A1 (fr) 1999-05-27 2000-12-07 Celltek Biotechnologies Inc. Antagonistes ccr3 de recepteurs de chimiokine
WO2000076933A2 (fr) 1999-06-10 2000-12-21 Ergon, Inc. Compositions de platre resistantes a l'eau
WO2001009088A1 (fr) 1999-07-28 2001-02-08 Kirin Beer Kabushiki Kaisha Derives d'uree utilises comme inhibiteurs du recepteur ccr-3
WO2002030357A2 (fr) 2000-10-11 2002-04-18 Chemocentryx, Inc. Composes et procedes servant a moduler la fonction de ccr4
WO2002030358A2 (fr) 2000-10-11 2002-04-18 Tularik Inc. Modulation de fonction de ccr4
WO2003029218A1 (fr) * 2001-09-28 2003-04-10 Kureha Chemical Industry Company, Limited Compose azote et utilisation correspondante
WO2004024697A1 (fr) 2002-09-11 2004-03-25 Kureha Chemical Industry Company, Limited Composes amines et leurs utilisation
WO2004052862A1 (fr) 2002-12-10 2004-06-24 Ono Pharmaceutical Co., Ltd. Composes heterocycliques contenant de l'azote et leur utilisation medicale
WO2005085209A1 (fr) 2004-03-10 2005-09-15 Kureha Corporation Composé aminé basique et son usage
WO2006020415A1 (fr) 2004-08-02 2006-02-23 Smithkline Beecham Corporation Composes chimiques
WO2006020891A2 (fr) 2004-08-13 2006-02-23 Anormed Inc. Combinaisons de chimiokines pour mobiliser des cellules progenitrices/souches
WO2006023400A2 (fr) 2004-08-16 2006-03-02 Smithkline Beecham Corporation Composes chimiques
WO2006022454A1 (fr) 2004-08-27 2006-03-02 Ono Pharmaceutical Co., Ltd Composé contenant un groupe basique et utilisation
WO2006028896A2 (fr) 2004-09-02 2006-03-16 Smithkline Beecham Corporation Composes chimiques
WO2006034001A2 (fr) 2004-09-16 2006-03-30 Bristol-Myers Squibb Company Procedes de traitement de l'infection par vih
WO2006036816A2 (fr) 2004-09-24 2006-04-06 Smithkline Beecham Corporation Composes chimiques
US20060069122A1 (en) 2004-09-29 2006-03-30 Anormed Inc. Chemokine-binding heterocyclic compound salts, and methods of use thereof
WO2006048862A2 (fr) 2004-10-31 2006-05-11 Yeda Research And Development Co.Ltd. Utilisation d'une protease ou d'un inhibiteur de protease pour la preparation de medicaments
WO2006076131A2 (fr) 2004-12-17 2006-07-20 Smithkline Beecham Corporation Composes chimiques
JP2006188445A (ja) 2005-01-05 2006-07-20 Ono Pharmaceut Co Ltd 含窒素複素環化合物およびその医薬用途
WO2006074426A2 (fr) 2005-01-07 2006-07-13 Emory University Antagonistes de cxcr4 pour le traitement de l'infection due au vih
US20060160860A1 (en) 2005-01-20 2006-07-20 Taigen Biotechnology Synthesis of polyamine compounds
WO2006090853A1 (fr) 2005-02-25 2006-08-31 Ono Pharmaceutical Co., Ltd. Composé hétérocyclique azoté et utilisation médicale de celui-ci
WO2006096444A2 (fr) 2005-03-04 2006-09-14 Smithkline Beecham Corporation Composes chimiques
WO2006117011A1 (fr) 2005-05-02 2006-11-09 Polyphor Ltd. Conjugues colorants de peptidomimetiques fixes sur matrice
US20060281712A1 (en) 2005-06-14 2006-12-14 Chi-Feng Yen Pyrimidine compounds
WO2007008539A2 (fr) 2005-07-11 2007-01-18 Smithkline Beecham Corporation Composes chimiques
WO2007022385A2 (fr) 2005-08-18 2007-02-22 Novartis Ag Molécules se liant au cxcr4
WO2007027999A2 (fr) 2005-08-31 2007-03-08 Smithkline Beecham Corporation Composes chimiques

Non-Patent Citations (40)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, JOHN WILEY & SONS INC
"Molecular Design", vol. 7, 1990, HIROKAWA SHOTEN, article "Development of Drug", pages: 163 - 198
"Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS INC
"The Merck Manual of Diagnosis and Therapy", MERCK & CO.
ABDICHE ET AL.: "Analytical biochemistry", vol. 328, 2004, pages: 233 - 243
BIOORG. MED. CHEM. LETT., vol. 10, 2000, pages 1803
BLOOD, vol. 102, 2003, pages 2728 - 2730
BLOOD, vol. 97, 2001, pages 3354 - 3360
CANCER RES., vol. 62, 2002, pages 1832 - 1837
CANCER RES., vol. 62, 2002, pages 3106 - 3112
CANCER RES., vol. 62, 2002, pages 5930 - 5938
CELL, vol. 52, 1985, pages 631
CIRC. RES., vol. 86, 2000, pages 131 - 138
DEVELOPMENT, vol. 129, 2002, pages 4249 - 4260
HUMAN SCIENCE SYNTHETIC RESEARCH PROMOTION BUSINESS FOCUSING ON DRUG INNOVATION IN FISICAL, 2003
IMMUNOLOGY, vol. 107, 2002, pages 222 - 232
J. CLI. INVEST., vol. 114, 2004, pages 438 - 446
J. CLI. INVEST., vol. 115, 2005, pages 86 - 93
J. EXP. MED., vol. 185, 1997, pages 111 - 120
J. IMMUNOL., vol. 165, 2000, pages 499 - 508
J. IMMUNOL., vol. 165, 2000, pages 6590 - 6598
J. IMMUNOL., vol. 167, 2001, pages 4648 - 4692
JOURNAL EXPERIMENTAL MEDICINE, vol. 2001, 2005, pages 1307 - 1318
MOL CANCER THER., vol. 5, 2006, pages 2592 - 9
NAT. MED., vol. 12, 2001, pages 1339
NATURE MEDICINE, vol. 4, 1998, pages 72
NATURE, vol. 382, 1996, pages 635 - 639
NATURE, vol. 382, 1996, pages 829
NATURE, vol. 382, 1996, pages 833
NATURE, vol. 393, 1998, pages 591 - 594
NATURE, vol. 393, 1998, pages 595 - 599
NATURE, vol. 410, 2001, pages 50 - 56
PROC- NAT. ACAD. SCI. USA, vol. 100, 2003, pages 13513 - 13518
RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, JOHN WILEY & SONS INC
SATO ET AL., YAKUBUTUDOTAI, XENOBIO. METABOL. AND DISPOS., vol. 16, no. 2, 2001, pages 115 - 126
SCIENCE, vol. 272, 1996, pages 1955
SCIENCE, vol. 272, 1996, pages 872
See also references of EP2042503A4
TRENDS IN NEUROSCIENCE, vol. 25, 2002, pages 548 - 549
ZOU ET AL., BIOPHYS. J., vol. 74, 1998, pages 230 - 241

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2055705A1 (fr) * 2006-07-31 2009-05-06 Ono Pharmaceutical CO., LTD. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
EP2055705A4 (fr) * 2006-07-31 2014-08-20 Ono Pharmaceutical Co Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
WO2010147094A1 (fr) * 2009-06-16 2010-12-23 小野薬品工業株式会社 Composé ayant un groupe cyclique à liaison spiro et son utilisation
JPWO2010147094A1 (ja) * 2009-06-16 2012-12-06 小野薬品工業株式会社 スピロ結合した環状基を有する化合物およびその用途
US8476290B2 (en) 2009-06-16 2013-07-02 Ono Pharmaceutical Co., Ltd. Compound having spiro-bonded cyclic group and use thereof

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EP2042503B1 (fr) 2013-01-30
US20090192182A1 (en) 2009-07-30
JP5257068B2 (ja) 2013-08-07
US8618122B2 (en) 2013-12-31
EP2042503A4 (fr) 2011-08-10
TW200813052A (en) 2008-03-16
EP2042503A1 (fr) 2009-04-01
JPWO2007132846A1 (ja) 2009-09-24

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